Kinases as targets in the treatment of solid tumors

Cellular Signalling 22 (2010) 984–1002 Contents lists available at ScienceDirect Cellular Signalling j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c e l l s i g Review Kinases as targets in the treatment of solid tumors Georgios Giamas a, Yik L. Man a, Heidrun Hirner b, Joachim Bischof b, Klaus Kramer b, Kalimullah Khan b, Sharmeen S. Lavina Ahmed a, Justin Stebbing a, Uwe Knippschild b,⁎ a b Department of Cancer and Surgery, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 ONN, UK Department of General-, Visceral- and Transplantation Surgery, University of Ulm, Germany a r t i c l e i n f o Article history: Received 23 December 2009 Accepted 13 January 2010 Available online 21 January 2010 Keywords: Kinases Solid tumors Kinase inhibitors Cancer a b s t r a c t The protein kinase family, one of the largest gene families in eukaryotes, plays an important role in regulating various cellular processes such as cell proliferation, cell death, cell cycle progression, differentiation and cell survival. Therefore, it is not surprising that the deregulation of many kinases is usually directly linked to cancer development. In all solid tumors, changes in protein kinase expression levels and activities, as well as alterations in the degree of posttranslational modifications can contribute to cancer development. Consequently, the identification of molecular targets and signaling pathways specific to cancer cells is becoming more and more important for cancer drug development and cancer therapies. Inhibition of various protein kinases has already been investigated in many pre-clinical and clinical trials targeting all stages of signal transduction, demonstrating promising results in cancer therapy. Conventional chemotherapeutics are often ineffective as well as harmful; hence a combination of both chemotherapeutics and protein kinase inhibitors may result in new and more successful therapeutic approaches. In this review we focus on protein kinases involved in different signaling pathways and their alterations in solid tumors. © 2010 Elsevier Inc. All rights reserved. Contents 1. 2. 3. Introduction . . . . . . . . . . . . . . . . . SMIs . . . . . . . . . . . . . . . . . . . . . Kinases in solid tumors . . . . . . . . . . . . 3.1. Lung cancer . . . . . . . . . . . . . . 3.2. Esophageal cancer . . . . . . . . . . . 3.3. Gastric cancer . . . . . . . . . . . . . 3.4. Liver cancer . . . . . . . . . . . . . . 3.5. Colorectal cancer. . . . . . . . . . . . 3.6. Pancreatic cancer . . . . . . . . . . . 3.7. Adrenocortical carcinoma. . . . . . . . 3.8. Kidney cancer . . . . . . . . . . . . . 3.9. Bladder cancer . . . . . . . . . . . . . 3.10. Endometrial, cervical and ovarian cancer 3.11. Prostate cancer . . . . . . . . . . . . 3.12. Breast cancer . . . . . . . . . . . . . 3.13. Sarcomas . . . . . . . . . . . . . . . 3.13.1. GIST . . . . . . . . . . . . . 3.13.2. Other sarcomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985 985 985 985 987 987 991 992 993 994 994 994 995 995 996 996 996 997 Abbreviations: SMI, Small molecule inhibitor; SCLC, Small cell lung cancer; SCC, Squamous cell carcinoma; TKI, Tyrosine kinase inhibitor; GEJ, Gastro esophageal junction; IGF1R, Insulin-like growth factor receptor; HCC, Hepatocellular carcinoma; CRC, Colorectal cancer; AC, Adenocarcinoma; ACC, Adrenocortical carcinoma; PKC, Protein kinase C; AChR, acetylcholine receptor; RCC, Renal cell carcinoma; GIST, Gastrointestinal stromal tumors; DFSP, Dermatofibrosarcoma protuberans; ES, Ewing Sarcoma. ⁎ Corresponding author. Department of General-, Visceral- and Transplantation Surgery, University of Ulm, Steinhövelstr. 9, 89075 Ulm, Germany. Tel.: + 49 731 500 53580; fax: + 49 731 500 53582. E-mail addresses: georgios.giamas@imperial.ac.uk (G. Giamas), y.man@ucl.ac.uk (Y.L. Man), heidrun.hirner@uniklinik.ulm.de (H. Hirner), joachim.bischof@uniklinik-ulm.de (J. Bischof), klaus.kramer@uniklinik-ulm.de (K. Kramer), kalimullah.Khan@uniklinik-ulm.de (K. Khan), sharmeen.ahmed07@imperial.ac.uk (S.S. Lavina Ahmed), j.stebbing@imperial.ac.uk (J. Stebbing), uwe.knippschild@uniklinik-ulm.de (U. Knippschild). 0898-6568/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.cellsig.2010.01.011 G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 4. Conclusion/future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction Cancer is a leading cause of death worldwide, being responsible for 13% of all deaths in 2005. According to recent estimates, the number of people diagnosed with cancer will increase from 1.6 million in 2010 to 2.3 million in 2030 in the United States [1]. Although great progress has been made in cancer research, there is still need for identification of new target molecules and development of novel therapeutic techniques. The protein kinase family, encompassing more than 500 members, represents an important therapeutic target for drug development. Through reversible phosphorylation, protein kinases take part in intracellular signal transduction processes such as metabolism, cellcycle progression, proliferation, apoptosis and differentiation. Thus far, more than 150 protein kinases have been shown to be involved in the development of human disorders and diseases, especially rheumatoid arthritis, cardiovascular diseases, immunodeficiency, endocrine disorders, neurodegenerative diseases and cancer [2]. Deregulation of several signal transduction pathways has been shown to play an important role in cancer development. This includes the WNT-pathway (reviewed in [3–6]), the Notch and hedgehog pathways, (reviewed in [7–9]), the TGF-β/BMP pathway (reviewed in [10–13], the RAS/RAF/MAP-kinase pathway (reviewed in [14–16]), the PI3K/AΚΤ pathway (reviewed in [17,18]), the JAK/STAT pathway (reviewed in [19,20]), and CK1, CK2, cyclin-dependent kinases and protein kinase C (PKC) dependent pathways (reviewed in [21–26]). Given that protein kinases have emerged as key regulators of all aspects of neoplasia, including proliferation, invasion, angiogenesis and metastasis, the development of potent and selective kinase inhibitors for molecular targeted cancer treatment is considered imperative [27–29]. In particular, the development of kinase inhibitors and drugs exerting different effects in order to overcome the ability of tumor cells to exploit overlapping pathways during progression has become the main focus of research in recent years [30,31]. Inhibitory compounds can be mainly classified into monoclonal antibodies and small-molecule inhibitors (SMIs). Monoclonal antibodies provide an attractive way to target receptor tyrosine kinases (e.g. EGFR and VEGFR), but their use is limited by their size, heterogeneous antigen expression and expression of targeted antigens in normal cells. 2. SMIs SMIs are offering some distinct advantages; among these, i) their mechanism of action is well understood, ii) they normally have less adverse effects than common chemotherapeutics although occasionally severe side effects have been described (see Table 1) and iii) the majority of SMIs can be administered orally, which simplifies delivery. However, the high cost of SMIs is a major drawback. SMIs can act on protein kinases by binding to the ATP-binding site of the active/inactive conformation of the enzyme (SMI type I and II). Although selective binding can be achieved, molecules targeting the ATP-binding site have been shown to be more cytotoxic due to the risk of non-specific inhibition of other cellular kinases [32]. Inhibitors binding to allosteric sites (belonging to SMI type III) show the highest degree of selectivity since the binding sites and regulatory mechanisms targeted by these inhibitors are unique for particular kinases. CI-1040 represents the best characterized allosteric inhibitor specific for MEK1 and MEK2. Threedimensional structure analyses of MEK1 and 2 have shown to have hydrophobic binding pockets adjacent to magnesium ATP binding site when they bind to MgATP and CI-1040-like inhibitors. As CI-1040 binds 985 997 997 997 to this site, it is thought to initiate conformational change in unphosphorylated MEK, resulting in its inactivation [33]. Studies have demonstrated that CI-1040 inhibits MEK1 in vitro, while in vivo CI1040 has antitumor activity in various models such as pancreas, colon and breast. This inhibitor was therefore the first MEK-targeted agent to enter clinical trials [33].The fourth class of inhibitor molecules (SMI type IV) acts by covalently binding to the kinase active site resulting in the abolition of kinase activity [34]. Another mechanism of inhibiting kinase signaling is by targeting the expression of a kinase gene or the maturation and correct folding of the kinase protein. Other strategies may influence the stability of the kinase itself or may lead to phosphatase activation for accelerated removal of substrate phosphates [35]. The action of SMIs is not limited to the tumor site. Astonishingly, inhibition of kinase activity in normal cells is largely well tolerated. This therefore provides a therapeutic window to specifically kill tumor cells [34]. However, side effects are unavoidable as with any other drugs. The large majority of SMIs are associated with frequent, but mild side effects, including fatigue, diarrhea and some form of skin rash. For example, a phase III study of Gefitinib involving patients with pulmonary adenocarcinoma found that 66% had rash or acne and 47% had diarrhea [36]. However, there are more specific adverse events associated with certain SMIs (Table 1). Interstitial lung disease occurs in approximately 1% of patients treated with Gefitinib or Erlotinib [37]. The VEGFR inhibitors, Sunitinib and Sorafenib, are associated with an increased risk of bleeding [38]. Imatinib, Dasatinib, Sunitinib, Sorafenib and Lapatinib can lead to cardiac toxicity, which can range from simple ECG changes to more severe conditions, such as congestive heart failure and acute coronary syndrome [39]. Fortunately, many SMIs actually have a more favourable side effect profile than conventional chemotherapeutics, whose efficacy is limited by their toxicity. Due to the rapid proliferation of cancer cells and selective pressure to acquire resistance to anticancer drugs, the mutation(s) of a kinase gene, which abolishes binding of inhibitory molecules, is a common problem (referred to as primary resistance) [40]. Mutation of the ‘gatekeeper residue’ as a mechanism of secondary resistance, normally does not affect kinase activity but may prevent the accessibility of a hydrophobic pocket near the ATP binding site. Since hydrophobic interactions in this site are essential for binding of the inhibitory molecules, this mutation leads to inhibitory resistance in many cases. Additionally, target amplification and up-regulation of alternative kinase pathways have been reported as non-mutation kinase inhibitory mechanisms leading to secondary resistance. In order to inhibit kinase inhibitor-resistant mutants, it is necessary to develop inhibitors either tolerating multiple amino acid changes in the gatekeeping position or binding to alternative binding sites [34]. With regards to the up-regulation of alternative kinase pathways, simultaneous use of more than one SMI or generation of SMIs targeting more than one kinase with nanomolar potency may prove practical in the future [41]. The large majority of kinase inhibitor discovery is currently dependent on rational drug design as opposed to high-throughput screening [34]. 3. Kinases in solid tumors 3.1. Lung cancer Two different histological types of lung cancer have been characterized so far: the small cell lung cancer (SCLC) and the non- 986 G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 Table 1 Side effects and organ toxicity of protein kinase inhibitors observed in clinical studies. Indicated substances (*) are already approved by the Food and Drug Administration (FDA) of the United States. Abbreviations: mAb: monoclonal antibody, ALL: acude lymphocytic leukaemia, CML: chronic myeloid leukaemia, CRC: colorectal cancer, GIST: gastrointestinal stromal tumor, NSCLC: non-small cell lung cancer, Ph+: Philadelphia-chromosome positive, RCC: renal cell carcinoma, TKs: tyrosine kinases, Btk: Bruton's tyrosine kinase, CSF1R: colony stimulating factor 1 receptor, EGFR: epidermal growth factor receptor, FLT: fms-like tyrosine kinase receptor, mTOR: mammalian target of rapamycin, PDGFR: platelet derived growth factor receptor, PI3K: phosphatidylinositol 3-kinase, PKC: protein kinase C, VEGFR: vascular endothelial growth factor receptor, CNS: central nervous system, GI: gastrointestinal, CMR: carcinogenic, mutagenic, toxic to reproduction. Kinase inhibitor Tumor entity/tumor stadium SMI target Side effects Literature Imatinib⁎ Ph+ CML (since 2001), GIST (since Dec 2008) dermatofibrosarcoma protuberans (since Oct 2006), Ph+ ALL (since Oct 2006) TKs (BCR-ABL) c-KIT, PDGFR [360–362] Nilotinib* (AMN107) Imatinib resistant CML (since Oct 2007), ALL, GIST BCR-ABL Sunitinib* Advanced RCC (since Jan 2006), Imatinib resistant GIST (since Jan 2006), advanced hepatocellular cancer, pancreatic neuroendocrine tumors, NSCLC TK, VEGFR1 + 2; PDGFRα + β, c-KIT, FLT3, RET, CSF1R Erlotinib* Advanced/metastatic NSCLC after failure of at least one chemotherapy regimen (since Nov. 2004) + gemcitabine in advanced/metastatic pancreatic cancer (since Nov 2005) Advanced RCC (since Oct 2009) Metastatic RCC (since Dec 2005), advanced hepatocellular carcinoma (since Nov 2007) EGFR Severe skin rash, high fever, diarrhea, hypo-, hyper-, and depigmentation, hypophosphataemia, hypocalcemia, leads to decreased circulation of Ca2+-phosphate, osteolysis, musculoskeletal and joint pain, muscle cramps, oedema, gastrointestinal symptoms Rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting, grade 2/4 toxicities include thrombocytopenia, neutropenia, elevated lipase, hyperglycemia, hypophosphatemia prolonged QT interval, sudden death clinical data on off-label indications and in patients with Ph+ ALL and GIST continue to emerge QT interval alterations, ventricular arrhythmias, fatigue, diarrhea, anorexia, nausea, vomiting, bleeding events, hyperthyroidism, hypertensive activity, skin adverse effects, posterior leukoencephalopathy Rash, diarrhea, vomiting, fatigue, anorexia, interstitial lung disease, liver function test abnormalities, hyperbilirubinaemia, infections, stomatitis, neutropenia, thrombocytopenia Diarrhea, hypertension, hair depigmentation, nausea Hand-foot–skin reactions, anorexia, alopecia, weight loss, abdominal pain Generally well tolerated, rash, diarrhea, < 1% interstitial lung disease (ILD), haematological and neurological rarer compared to chemotherapy regimens Well tolerated, nausea, vomiting, lymphopenia [36,37] Pazopanib* Sorafenib* Gefitinib* NSCLC with EGFR mutations (since May 2003) Saracatinib Indication by metastatic cancer with increased (AZD0530) bone resorption Danuserbib Solid tumors refactory to standard therapy (PHA-739358) Advanced and metastatic solid tumors Advanced metastatic breast cancer Advanced solid cancers Advanced solid tumors, Breast cancer, NSCLC EGFR, HER2 Nausea, vomiting, fatigue, anorexia NSCLC tumors with activating mutations in EGFR kinase domain. Advanced metastatic breast cancer EGFR, HER2 Gastrointestinal and cutaneous disorders ErbB + capecitabine, advanced/metastatic breast cancer HER2+ (since Mar 2007) EGFR, HER2 Dose dependent grades 3–4 adverse events include diarrhea, asthenia, and stomatitis Diarrhea, nausea, vomiting, rash, palmar–plantar erythrodysesthesia, reversible decreased left ventricular function, anaemia, neutropenia, thrombocytopenia Imatinib resistant CML (since June 2006) CP-868,596 ABT-869 Advanced solid tumors Solid tumors refractory to standard therapy Vandetanib (ZD6474) NSCLC, medullary thyroid cancer Telatinib Advanced metastatic solid tumors Axitinib Advanced NSCLC Temsirolimus* Advanced RCC (since May 2007) Everolimus* Advanced RCC after failure of Sunitinib or Sorafenib (since March 2009) Metastatic CRC (since Feb 2004), RCC, NSCLC, HER2 negative breast cancer, glioblastoma multiforme HER2+ breast cancer (since Sept 1998) Endometrial cancer Masitinib Triciribine UCN-01 (NSC 638850) Neratinib (HKI-272) BIBW-2992 CI-1033 Lapatinib* Src Neutropenia, nausea, anorexia, fatigue, diarrhea, mild to moderate nonhematologic toxicity, neutropenia dose limiting TKs (BCR-ABL) Src, Substantial, sometimes severe side effects, body weight Lyn, Btk loss, pleural effusions grade 2 and higher, infections, skin cancer development PDGFR Grade 1 + 2 severity: nausea, vomiting, diarrhea Multiple receptor TKs Grade 3 fatigue, grade 3 hypertension, grade 3 proteinurea, asthenia, hand and foot blisters, myalgia EGFR, VEGFR, RET Rash, diarrhea, hypertension, fatigue, asymptomatic QT prolongation, cutaneous hyperpigmentation after photosenibility VEGFR2 + 3, PDGFR-β, Nausea, hypotension (grades 3–4), grade 2 weight loss, c-KIT anorexia, fatigue VEGFR1, 2, 3 Grade 3 treatment adverse effects ≥ 5%, fatigue, hypertension, hyponatremia mTOR Hyperglycemia, hyperlipidemia, skin toxicity and stomatitis, pneumonitis mTOR Hyperglycemia, hyperlipidemia, hypercholesterolemia, stomatitis, rash, diarrhea, pneumonitis VEGFR Gastrointestinal perforation, wound healing complications, fistula formation, stratus, hypertention HER2 Cardiac dysfunction — ventricular dysfunciton, congestive heart failure (especially in combination with anthracyclines) diarrhea, anaemia, neutropenia, upper respiratory infections, anaphylaxis, hypotension, dyspnoea, acute respiratory distress syndrome, angioedema c-KIT Grades 1–2 treatment adverse effects AKT Hypertriglyceridemia and fatigue, cardiomyopathy Chk1 Subarachnoid hemorrhage, hyperglycemia, hypoxia Dasatinib* Bevacizumab (mAb)* Trastuzumab (mAb)* PDGFR, VEGFR, c-KIT Multikinase inhibitor, PDGFR, VEGFR, c-KIT and Ser/Thr pecific kinases, e. g. Raf1 TK, EGFR Aurora kinase [363,364] [365–370] [37,55,371] [372] [367,373– 375] [376,377] [378] [379,380] [381] [382,383] [384–386] [387] [388] [367] [367,389,390] [367] [391,392,408] [393,409] [394,410] [395,396, 411,412] [397,398, 413,414] [399,415] [400,401, 416,417] [402,403, 418,419] 987 G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 Table 1 (continued) Kinase inhibitor Tumor entity/tumor stadium SMI target Side effects Literature Cedirnanib Advanced NSCLC tumors VEGFR1, 2, 3 Motesanib Advanced or metastatic medullary thyroid cancer [404,405, 420,421] [406,422] Enzastaurin CRC VEGFR1, 2, 3, c-KIT, PDGFR PI3K, PKC Hypertension, hypothyroidism, hand–foot syndrome, GI toxicity Diarrhea, fatigue, hypothyroidism, hypertension, anorexia Remarkable toxicity profile [407,423] small cell lung cancer (NSCLC). NSCLC represents the largest group (85%), which can be divided into squamous cell carcinomas (SCC), adenocarcinomas (AC), large cell carcinoma and other types [42]. Several oncogenic mutations in protein kinases have been found in malignancies of the lung, including mutations in KRAS, HER2 or EGFR, which may occur individually but not cooperatively. An over-expression of EGFR has been detected in patients with NSCLC which is associated with a poor prognosis and correlates with somatic mutations in EGFR (see Table 2) [43–47]. Two research groups have identified mutations in the tyrosine kinase binding domain of EGFR in patients with adenocarcinomas, which more frequently affect nonsmokers, people from East Asia and women [48,49]. EGFR signaling can be blocked using specific EGFR inhibitors like Gefitinib (Iressa®, AstraZeneca), Erlotinib (Tarceva®, OSI Pharmaceuticals) and Lapatinib (Tykerb®, GlaxoSmithKline), which interfere with the tyrosine kinase domain [50]. These inhibitors are already approved or in phase III clinical trails (see also Tables 1 and 3 and Fig. 1), in which female patients, nonsmokers, East Asian people and patients with lung adenocarcinomas showed a higher response rate [51–54]. Recently, two different studies revealed that after Gefitinib therapy, followed by either gemcitabine/ platinum based combination regimen or Erlotinib therapy, there was an improved overall survival rate [55,56]. Investigation of 120 primary lung tumors indicated that 4% bear mutations in HER2 while 10% of the examined adenocarcinomas were positive for HER2 mutations [57]. Previously, mutations in KRAS, especially G→T transversions that result in an activation of KRAS protein, were found only in patients who smoked. However, a recent study from Riely and co-workers indicated that this mutation can also occur in non-smokers [53,58,59]. Furthermore, over-expression of HER2 protein in NSCLC has been linked to poor survival prognosis as well as co-expression of HER2 and EGFR [60]. Moreover, over-expression of MET, a tyrosine kinase receptor, has been identified in NSCLC, which leads to an activation of the PI3K/AKT pathway and therefore to resistance to Gefitinib [61,62]. In NSCLC, particularly adenocarcinomas, the expression of Src is up-regulated and correlates with tumor size [63]. STAT-3 and JAK are both activated by Src in NSCLC, thereby activating Src-mediated pathways [64]. In addition, Src can activate EGFR through phosphorylation, resulting in oncogenesis [65–67]. The investigations of Src inhibitors as potential therapies for NSCLC are currently ongoing. Among them, Dasatinib, a small molecule inhibitor, already in preclinical trials showed promising results as it decreases cell growth and reduces cell invasion [68,69]. 3.2. Esophageal cancer Esophageal cancer is the sixth leading cause of cancer death worldwide [70]. There are two major histological sub-types; SCC in the upper or middle third of the esophagus, and adenocarcinoma in the lower third. In Western countries, the incidence of adenocarcinoma has risen, relating it to the increase in obesity, chronic gastric reflux and Barrett's esophagus [71]. Poorly differentiated esophageal adenocarcinomas have higher EGFR expression levels than low-grade tumors [72]. Over-expression of EGFR also occurs in 50% of esophageal SCCs, and correlates with the depth of tumor invasion [73]. Mutations in EGFR have also been identified in esophageal cancer (see Table 2) [74,75]. In esophageal SCC cell lines, Gefitinib has been shown to inhibit RAS/RAF/MAPK and PI3K/AKT downstream signaling pathways, leading to growth inhibition and apoptosis [76]. Gefitinib has also been evaluated in several phase II trials and is considered a promising second-line treatment for advanced esophageal cancer. More precisely, Janmaat et al. [77] demonstrated that Gefitinib was more effective in patients with SCC histology and high expression of EGFR, while Ferry et al. [78] found that there was a disease control rate of 37% and 5 of 7 biopsies taken post-treatment showed a significant reduction of Ki67. Finally, administration of Erlotonib in a phase II clinical trial involving 20 patients with esophageal cancer, where 15 patients had EGFR over-expression, resulted in 8 patients having stable disease, while 3 patients achieved partial response (all SCC histology) [79]. Amplifications of HER2/neu have been reported in 15% of esophageal adenocarcinomas and 5% of esophageal SCC (Table 2). Akamatsu et al. [80] found that the expression of HER2/neu in patients with esophageal SCC predicts chemo-radio-resistance, but does not correlate with survival. Phase II clinical trials of Lapatinib in esophageal cancers are in progress [70]. Evidence from various studies shows that VEGF is over-expressed in 24–69% of esophageal SCCs [81–84]. Shimada et al. [85] found that elevated serum levels of VEGF in patients with esophageal SCC were associated with tumor progression, poor treatment response and poor survival. Over-expression of Cyclin D1 has also been detected in patients with esophageal SCC [81,86]. However, use of the CDK inhibitor Flavopiridol in 3 separate phase I trials had no effect in patients with esophageal cancer [87–89]. 3.3. Gastric cancer Gastric cancer is the second most common cause of cancer death in males worldwide and fourth in females [71] with an incidence of over one million cases in 2007. Gastric cancer and cancer of the gastro-esophageal junction (GEJ) are histo-pathologically and genetically heterogeneous diseases [90]. 95% of the malignant tumors of the stomach are adenocarcinomas, originating from the glandular epithelium of the gastric mucosa. Lauren classified gastric cancer into two major types based on their histology; intestinal-type (well differentiated tumor) and diffusetype (poorly differentiated tumor), but this does not account for all gastric cancers [91]. Infection with H. pylori is a well-established risk factor and leads to an approximate 2-fold increased risk of gastric cancer [92]. Recently, Mita et al. [93] used a novel method (digital genome scanning) and detected amplification of the KRAS locus in 15% of gastric cancer cell lines (8–18 fold amplification) and in 4.7% of primary gastric tumors (8–50 fold amplification). There was a direct correlation between increased KRAS copy number and over-expression of KRAS protein. Significantly, they showed that in gastric cancer cells in which wild-type KRAS was amplified, knock-down of KRAS by siRNA leads to cell growth inhibition and suppression of p44/42 MAPK and AKT activities. Aurora kinase A (AURKA), playing important roles in the regulation of centrosome separation and chromosome segregation [94,95], is over-expressed in 47% of upper gastrointestinal adenocarcinomas preventing apoptosis by reducing the transcriptional activity of p53 via the AKT/HDM2 axis [96]. HER2/neu gene amplification is present in 12.2% of gastric and 24.0% of GEJ adenocarcinomas (see Table 2). It is more common in the 988 G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 Table 2 Alterations observed in oncogenic kinases and resulting malignancies. Kinase Observed alterations Serine/threonine kinases Akt amp, OE, act Aurora A and B Chk1 Chk2 ERK5 MEK1,2 mTOR Polo-like kinases PI3K B-Raf c-Raf KRAS amp, OE, SNP mut mut act mut, OE act, OE OE mut, act mut amp amp, mut Non-receptor tyrosine kinases Abl trans FAK amp, OE, act JAK2 mut, trans Src OE, mut, act Receptor tyrosine kinases Alk mut, amp EGFR-family EGFR (ErbB1) amp, OE, mut Her2 (ErbB2) amp, OE Her3 (ErbB3) Her4 (ErbB4) FGFR-family FGFR1 FGFR2 FGFR3 FGFR4 trans mut, amp mut, trans, act SNP FLT3 IGF-1R and IGF-2R c-KIT Met ITD OE, act mut, act, OE mut, OE, trans PDGFR-family PDGFR-α PDGFR-β Ret VEGFR-family VEGFR1 VEGFR2 OE OE, downregulation Tumor entity Breast [250-252], prostate [227], lung [61, 62], pancreatic [171-173], liver, ovarian [302], colorectal cancer [143, 144] Breast [303], gastric [94, 95] and colorectal cancer [303], leukaemia [304] Gastric [305], colorectal [306] and endometrial cancer [306] prostate [307] and breast cancer [308], variety of sporadic cancers and cell lines [309] Breast [310] and prostate cancer [311] multiple tumors Renal cell carcinoma [312], pancreatic cancer [177, 178] Breast [313], lung [314] and colon cancer [315], lymphoma Colon [133, 134], breast [240][240], prostate [217], bladder [316], gastric cancer [317], glioblastoma [318] Melanoma [319], colon cancer [320] Bladder [321], prostate [322], nasopharyngeal cancer Lung [58, 59], gastric [93], colorectal [137, 138] and endometrial cancer [211] CML [323] Breast [333], ovarian [334], hepatocellular [335], thyroid cancer [336] CML [351], MPD Colon [153, 154], endometrial, breast [247, 248], pancreas, lung [63], ovarian [357], prostate [234] and CNS cancer ALCL [324], lung cancer [325], neuroblastoma [326] Breast [245], esophageal [72-75], gastric [105], liver [121], pancreatic [174, 175], ACC [195, 196], head and neck cancer [327], lung [43-47], ovarian [217], prostate [224], bladder [207] and colon cancer, glioblastoma [328] Breast [239], lung [57], esophageal [80], gastric [97], pancreatic [175], ovarian [329] and endometrial cancer [213], glioblastoma [330] Breast [240] and other tumors Head and neck cancer, renal cell carcinoma [331], papillary carcinoma, glioma, breast cancer [332] CML [337] Gastric [110], breast [338], endometrial [339] and some B-cell cancers, glioblastoma Bladder [340], cervical [341] and colorectal cancer [342], multiple myeloma Breast [343], pancreatic [344], prostate [116], head and neck cancer [345] and soft tissue sarcomas [346], pituitary adenomas [347] AML [348] Gastric [105], pancreatic [349], endometrial [211] and colorectal cancer [350], ACC [191-193] GIST [273-275], other sarcomas [287-290], colorectal [149] and ovarian cancer [352] Papillary renal carcinoma, renal cell carcinoma [353], hepatocellular carcinoma [354], gastric carcinoma [99, 101], lung cancer (NSCLC) [61, 62] trans, OE , mut, del trans, OE mut, trans GIST [277], ovarian cancer [352], glioblastoma Multiple tumors, ovarian cancer [352], CML Familial medullary thyroid carcinoma (FMTC), multiple neoplasia type IIA (MEN2A, MEN2B) [355], thyroid cancer [356] OE, downregulation mut, OE Several tumor types, prostate cancer [358] Capillary infantile hemangioma, liver [115, 116] and colon cancer [359] Abbreviations: Chk: Checkpoint kinase, ERK5: extracellular signal-regulated kinase 5, mTOR: mammalian target of rapamycin, PI3K: phosphatidylinositol 3-kinase, Abl: v-abl Abelson murine leukaemia viral oncogene homolog 1, Alk: anaplastic lymphoma kinase, EGFR: epidermal growth factor receptor, FAK: focal adhesion kinase, FGFR: fibroblast growth factor receptor, FLT3: fms-like tyrosine kinase receptor-3, IGF-1R: insulin-like growth factor 1 receptor, JAK2: Janus kinase 2, MET: mesenchymal–epithelial transformation factor/ hepatocyte growth factor receptor, PDGFR: platelet derived growth factor receptor, VEGFR: vascular endothelial growth factor receptor, amp: amplification, OE: overexpression, act: activation, SNP: single nucleotide polymorphism, mut: mutation, trans: translocation, ITD: internal tandem duplication, del: deletion, CML: chronic myeloid leukaemia, ALCL: anaplastic large-cell lymphoma, ACC: adrenocortical carcinoma, AML: acute myeloid leukaemia, MPD: myeloproliferative disorder, GIST: gastrointestinal stromal tumors, NSCLC: non-small cell lung cancer, CMML: chronic myelomonocytic leukaemia. intestinal-type of gastric cancer, and co-amplification of topoisomerase II alpha has been reported in the majority of cases [97]. Lapatinib, a dual inhibitor of EGFR and HER2, inhibited the phosphorylation of EGFR, HER2 and downstream signaling proteins in two gastric cancer cell lines leading to G1 arrest and growth inhibition of the tumors [98]. Amplification of the MET gene has also been observed in gastric cancer. MET encodes the receptor tyrosine kinase for hepatocyte growth factor (HGF), leading to over-expression and activation of MET [99]. Binding of HGF to MET, followed by recruitment of the scaffolding proteins Gab1 and Grb2, results in activation of Shp2, RAS and ERK/MAPK. These events lead to specific changes in the cytoskeletal functions that are important during metastasis [100]. Over-expression of MET in gastric cancer represents an independent prognostic factor and therefore, an attractive drug target [101]. Bachleitner-Hofmann et al. [102] found that all gastric tumors which over-expressed MET, also co-expressed EGFR, HER3 or both. Treatment with the MET inhibitor PHA-665752 abolished MEK/MAPK and PI3K/AKT signaling and also inhibited MET-dependent EGFR and HER3 phosphorylation leading to growth inhibition. Interestingly, they found that MET-independent HER kinase activation could reverse growth inhibition by re-stimulating MEK/MAPK and PI3K/ AKT signaling. Importantly, cells treated with PHA-665752 and Gefitinib abolished this ‘escape mechanism’, showing that inhibiting MET and HER kinase signaling simultaneously may be important. Interim results from a phase II study showed that 2 out of 12 patients, with poorly differentiated gastric cancer, had a 20% reduction in tumor size after 8 weeks treatment with XL880, a dual inhibitor of MET and VEGFR2 [103]. Over-expression of EGFR has been observed in 27.4% of gastric carcinoma tissues; it is an indicator of poor prognosis as it is 989 G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 Table 3 Kinase inhibitor substances and according targets in clinical trials or approved for solid tumors. Data shown in table 3 were adopted from target intelligence service (TSI, www. targetintelligenceservice.com). Indicated targets are listed according to the respective mechanism of action of the given drugs. Abbreviations: Aur: aurora kinase, Chk: checkpoint kinase, EGFR: epidermal growth factor receptor, ERK: extracellular signal regulated kinase, FGFR: fibroblast growth factor receptor, IGF-1R: insulin-like growth factor 1 receptor, MEK: mitogen-activated protein kinase, mTOR: mammalian target of rapamycin, PDGFR: platelet derived growth factor receptor, PI3K: phosphatidylinositol 3-kinase, VEGFR: vascular endothelial growth factor receptor, (Y): monoclonal antibody, CNS: central nervous system, CRC: colorectal cancer, GIST: gastrointestinal stromal tumor, HM: haematologic malignancies, (N)SCLC: (non) small cell lung cancer. Target AKT Drug AEG 41174 RX 0201 Triciribine AurA, AurB AT 9283 AZD 1152 BI 811283 Danusertib MK 5108 MLN 8237 PF 03814735 R 763 SNS 314 Chk1 IC 83 PF 00477736 SCH 900776 Chk1, Chk2 AZD 7762 Chk2 CBP 501 c-Raf HE 3235 XL 281 c-Raf, VEGFR RAF 265 Regorafenib Sorafenib (Nexavar®) EGFR Aderbasib AE 37 ARRY 380 AV 412 AZD 4769 AZD 8931 BIBW 2992 (Tovok®) BMS 599626 Canertinib CUDC 101 Erlotinib (Tarceva®) GA 201 (Y) Gefitinib (Iressa®) Icotinib INSM 18 JX 929 Lapatinib (Tykerb®) Lapuleucel-T Leflunomide (Arava®) MM 111 Neratinib Pertuzumab (Y) PF 299804 PX 1032 (MVABN®) S 222611 TAK 285 Trastuzumab (Herceptin®) (Y) Varlitinib Zalutumumab (Y) EGFR, Src, VEGFR JNJ 26483327 AEE 788 EGFR, VEGFR BMS 690514 Vandetanib (Zactima®) XL 647 ERK5 AS 703026 ERK5, MEK1/2 RO 4987655 FAK PF 4554878 PF 562271 Originator Dev. stage Indication The Hospital for Sick Children Rexahn Pharmaceuticals University of South Florida Astex Therapeutics AstraZeneca Boehringer Ingelheim Nerviano Medical Sciences Vertex Pharmaceuticals Millennium Pharmaceuticals Pfizer Rigel Pharmaceuticals Sunesis Pharmaceuticals ICOS Corporation Pfizer Schering-Plough AstraZeneca CanBas Hollis-Eden Pharmaceuticals Exelixis Novartis Bayer HealthCare Onyx Pharmaceuticals Phase I Phase II Phase I Phase I Phase II Phase II Phase II Phase I Phase II Phase I Phase I Phase I Phase I Phase I Phase I Phase I Phase II Phase I Phase I Phase I Phase II launched Incyte Corporation Antigen Express Array BioPharma Mitsubishi Pharma Corporation AstraZeneca AstraZeneca Boehringer Ingelheim Phase Phase Phase Phase Phase Phase Phase Bristol-Myers Squibb Pfizer Curis OSI Pharmaceuticals Phase II Phase II Phase I launched GlycArt Biotechnology AstraZeneca Phase I launched Zhejiang Beta Pharma Insmed Jennerex GlaxoSmithKline Phase II Phase I Phase I launched Cancer, HM Renal cancer, pancreatic cancer Solid tumors, cancer, HM Solid tumors, HM, non-Hodgkin's lymphoma Solid tumors, HM, non-Hodgkin's lymphoma Solid tumors, HM, non-Hodgkin's lymphoma HM, multiple myeloma, prostate cancer Solid tumors Solid tumors, neuroblastoma, HM, non-Hodgkin's lymphoma, ovarian cancer Solid tumors Solid tumors, HM Solid tumors Cancer, pancreatic cancer Solid tumors Solid tumors, lymphoma Solid tumors Solid tumors, mesothelioma, NSCLC Breast cancer, prostate cancer Solid tumors Malignant melanoma, cancer Solid tumors, renal cancer, CRC Malignant melanoma, gastric cancer, liver cancer, chloangiocarcinoma, thyroid cancer, CRC, HM, renal cancer, NSCLC, ovarian cancer, breast cancer Solid tumors, breast cancer Breast cancer, ovarian cancer, prostate cancer Solid tumors, cancer Solid tumors Solid tumors Solid tumors Solid tumors, CRC, glioblastoma, head and neck cancer, NSCLC, breast cancer, prostate cancer Solid tumors Head and neck cancer, NSCLC, breast cancer, ovarian cancer Solid tumors Liver cancer, CRC, glioblastoma, head and neck cancer, NSCLC, bladder cancer, breast cancer, gynaecological cancer, pancreatic cancer, myelodysplastic syndromes Solid tumors CRC, glioblastoma, head and neck cancer, renal cancer, NSCLC, bladder cancer, breast cancer NSCLC Prostate cancer Solid tumors Solid tumors, gastric cancer, brain cancer, head and neck cancer, breast cancer Dendreon Corporation Sanofi-Aventis Phase I Launched CRC, breast cancer, ovarian cancer Anaplastic astrocytoma, NSCLC, ovarian cancer, prostate cancer, glioblastoma Merrimack Pharmaceuticals Wyeth Roche, Genentech Pfizer Pharmexa Phase Phase Phase Phase Phase Solid tumors Solid tumors, NSCLC, breast cancer NSCLC, breast cancer, ovarian cancer, prostate cancer Solid tumors, head and neck cancer, NSCLC Breast cancer Shionogi Takeda Genentech Phase I Phase I Launched Solid tumors Solid tumors, cancer Gastric cancer, NSCLC, breast cancer Array BioPharma Genmab Phase II Phase III Solid tumors, breast cancer CRC, head and neck cancer, NSCLC Janssen Pharmaceutica Novartis Bristol-Myers Squibb AstraZeneca Clinical Phase I Phase I Phase III Exelixis Santhera Pharmaceuticals Roche Pfizer Pfizer Phase Phase Phase Phase Phase Cancer, cancer metastases Solid tumors, glioblastoma Solid tumors, NSCLC Solid tumors, mesothelioma, SCLC, CRC, thyroid cancer, glioma, NSCLC, ovarian cancer, breast cancer, biliary cancer, prostate cancer Solid tumors, NSCLC Solid tumors Solid tumors Cancer Cancer II II I I I I III I III III II I II I I I I (continued on next page) 990 G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 Table 3 (continued) Target Drug Originator Dev. stage Indication FGFR, c-KIT, VEGFR FGFR, PDGFR, VEGFR ENMD 2076 Miikana Therapeutics Phase I Solid tumors, haematological malignancies, CRC, multiple myeloma BIBF 1120 (Vargatef®) Dovitinib Boehringer Ingelheim Phase III Solid tumors, CRC, NSCLC, ovarian cancer, prostate cancer Novartis Phase II AP 24534 AMG 479 (Y) Ariad Pharmaceuticals Amgen Phase I Phase II Anti-IGF-1R mAb (Y) AXL 1717 BIIB 022 (Y) Cixutumumab (Y) Figitumumab (Y) Genentech Phase I Malignant melanoma, HM, renal cancer, multiple myeloma, breast cancer, prostate cancer Cancer, haematological malignancies Solid tumors, cancer, CRC, SCLC, NSCLC, ovarian cancer, breast cancer, pancreatic cancer, sarcoma Solid tumors Axelar Biogen Idec ImClone Systems Phase I Phase I Phase II Pfizer Phase III MK 0646 (Y) Merck & Co Phase II OSI Pharmaceuticals Roche, Genmab Schering-Plough Phase III Phase II Phase II Cancer Solid tumors Solid tumors, liver cancer, CRC, head and neck cancer, NSCLC, breast cancer, prostate cancer, pancreatic cancer, soft tissue sarcoma Solid tumors, CRC, NSCLC, rheumatoid arthritis, gastrointestinal cancer, multiple myeloma, breast cancer, gynaecological cancer, prostate cancer, sarcoma Solid tumors, cancer, CRC, NSCLC, multiple myeloma, breast cancer, pancreatic cancer, neuroendocrine tumors Solid tumors, adrenocortical carcinoma, ovarian cancer Solid tumors, Hodgkin's disease, NSCLC, breast cancer, non-Hodgkin's lymphoma, sarcoma CRC, osteosarcoma, sarcoma Exelixis Novartis Phase I launched Cancer, HM Prostate cancer, scleroderma, HM, malignant melanoma, SCLC, glioblastoma, GIST AB Science SuperGen Exelixis Phase III Phase I Phase II GIST, pancreatic cancer Solid tumors, lymphoma, glioblastoma Solid tumors, gastric cancer, head and neck cancer, renal cancer Eisai Phase II Solid tumors, liver cancer, thyroid cancer, lymphoma, NSCLC Array BioPharma Array BioPharma Array BioPharma Phase I Phase I Phase II Array BioPharma Eisai Medical Research Exelixis Japan Tobacco Valeant Pharmaceuticals International Chugai Pharmaceutical Amgen ArQule Ortho Biotech Genentech MethylGene Merck & Co Merck & Co Pfizer Pfizer AVEO Pharmaceuticals Eisai Exelixis Novartis Novartis Phase Phase Phase Phase Phase Solid tumors Cancer Malignant melanoma, solid tumors, liver cancer, CRC, thyroid cancer, HM, NSCLC, multiple myeloma, ovarian cancer, biliary cancer, pancreatic cancer Solid tumors Solid tumors Solid tumors Cancer Cancer, inflammation Phase I Phase I Phase II Phase I Phase II Phase II Phase I Phase I Phase III Phase I Phase I Phase I Phase III Phase I launched Cleveland BioLabs OSI Pharmaceuticals Ariad Pharmaceuticals Concordia Pharmaceuticals Semafore Pharmaceuticals Wyeth Phase II Phase I Phase III Phase II Phase I Launched Wyeth Launched FGFR, VEGFR IGF-1R OSI 906 RG 1507 Robatumumab (Y) IGF-1R, Src XL 228 c-KIT Imatinib (Gleevec®) Masitinib c-KIT, Met, PDGFR MP 470 c-KIT, Met, GSK 1363089 PDGFR, VEGFR c-KIT, PDGFR, E 7080 VEGFR MEK1/2 ARRY 162 ARRY 300 AZD 6244 AZD 8330 E 6201 GDC 0973 GSK 1120212 RDEA 119 Met Met, VEGFR mTOR PDGFR PDGFR, VEGFR RG 7167 AMG 208 ARQ 197 JNJ 38877605 MetMAb (Y) MGCD 265 MK 2461 MK 8033 PF 2341066 PF 4217903 SCH 900105 (Y) E 7050 XL 184 BEZ 235 Everolimus (Afinitor®) Mepacrine OSI 027 Ridaforolimus Salirasib SF 1126 Sirolimus (Rapamune®) Temsilrolimus (Torisel®) Tandutinib Linifanib Midostaurin Motesanib Pazopanib Millennium Pharmaceuticals Abbott Laboratories Novartis Amgen GlaxoSmithKline SU 14813 SU 6668 Pfizer Pfizer I II I I I Solid tumors Solid tumors Solid tumors, liver cancer, renal cancer, NSCLC, pancreatic cancer Solid tumors NSCLC Solid tumors, NSCLC Solid tumors, cancer Cancer Cancer, NSCLC Cancer Solid tumors, lymphoma, multiple myeloma Solid tumors Cancer, thyroid cancer, glioblastoma, NSCLC Solid tumors, HM, glioblastoma, renal cancer, NSCLC Gastric cancer, liver cancer, renal cancer, breast cancer, pancreatic cancer, neuroendocrine tumors Prostate cancer Solid tumors, lymphoma Solid tumors, NSCLC, breast cancer, prostate cancer, endometrial cancer, sarcoma NSCLC, pancreatic cancer Solid tumors, multiple myeloma Cancer CRC, mantle cell lymphoma, glioblastoma, Hodgkin's disease, renal cancer, CNS cancer, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, soft tissue sarcoma Phase II Glioblastoma, Glioma, prostate cancer Phase II Liver cancer, CRC, HM, renal cancer, NSCLC, breast cancer Phase III CRC, HM, multiple myeloma, GIST Phase III Solid tumors, CRC, thyroid cancer, NSCLC, breast cancer, GIST Registered Liver cancer, CRC, cervical cancer, renal cancer, glioma, NSCLC, ovarian cancer, breast cancer, sarcoma Phase II Breast cancer Phase II Solid tumors, liver cancer, cancer, breast cancer G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 991 Table 3 (continued) Target Drug Originator Dev. stage Indication PDGFR, VEGFR TAK 593 ZK 304709 PX 866 Millennium Pharmaceuticals Bayer Schering Pharma Burham institute, University of Pittsburgh, University of Arizona Novartis Novartis Calistoga Pharmaceuticals Eli Lilly Phase I Phase I Phase I Solid tumors Cancer Solid tumors Phase Phase Phase Phase GDC 0941 GDC 0980 GSK 1059615 GSK 2126458 Mepacrine SF 1126 XL 147 XL 765 Bosutinib Dasatinib (Sprycel®) KX2 391 Saracatinib AZM 475271 Alacizumab pegol (Y) Axitinib Piramed Genentech GlaxoSmithKline GlaxoSmithKline Cleveland BioLabs Semafore Pharmaceuticals Exelixis Exelixis Wyeth Bristo-Myers Squibb Phase I Phase I Phase I Phase I Phase II Phase I Phase I Phase I Phase III Launched Kinex Pharmaceuticals AstraZeneca AstraZeneca UCB Phase Phase Phase Phase Solid tumors, HM, glioblastoma, renal cancer, NSCLC Solid tumors HM, non-Hodgkin's lymphoma CRC, glioblastoma, follicular lymphoma, NSCLC, multiple myeloma, lung cancer prevention, breast cancer, ovarian cancer, non-Hodgkin's lymphoma Solid tumors, NSCLC, non-Hodgkin's lymphoma, breast cancer Solid tumors, non-Hodgkin's lymphoma Cancer Cancer Prostate cancer Solid tumors, multiple myeloma Solid tumors Solid tumors, glioma Solid tumors, HM, breast cancer CRC, HM, NSCLC, multiple myeloma, breast cancer, non-Hodgkin's lymphoma, prostate cancer Cancer Solid tumors, bone cancer, ovarian cancer Solid tumors, haematological malignancies NSCLC Pfizer Phase III Brivanib alaninate Cediranib Bristol-Myers Squibb Phase III AstraZeneca Phase III CEP 11981 CT 322 IMC 18F1 (Y) JI 101 KRN 633 MGCD 265 OSI 930 OTS 102 PF 337210 Ramucirumab (Y) Sunitinib (Sutent®) Telatinib Tivozanib YN 968D1 Cephalon, Sanofi-Aventis Adnexus Therapeutics ImClone Systems Jubilant Innovation Kirin Brewery MethylGene OSI Pharmaceuticals OncoTherapy Science Pfizer Dyax Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Pfizer Launched Bayer Kirin Brewery Advenchen Laboratories Phase II Phase II Phase II PI3K BEZ 235 BGT 226 CAL 101 Enzastaurin PI3K, mTOR Src VEGFR I I I III I II II II I II I I I II I II I III associated with later disease stages and is more commonly detected in poorly differentiated tumors [104]. In a study involving 86 patients with advanced gastric cancer, 55% of surgically removed primary tumors were shown to over-express EGFR and type 1 insulin-like growth factor receptor (IGF-1R), which correlated with poor clinical outcome [105]. In a double-blind phase II trial, patients with gastric or GEJ adenocarcinoma were randomly assigned to receive Gefitinib. EGFR expression was detected in 58.6% of the baseline tumor biopsies. Although levels of phosphorylated EGFR were significantly reduced at 28 days post-treatment, levels of phosphorylated MAPK and AKT were not reduced. However, in some patients where AKT phosphorylation was reduced, there was enhanced apoptosis, indicating that a sub-set of gastric tumors are EGFR sensitive [106]. Patients with gastric adenocarcinoma also showed no response to Erlotinib treatment [107]. Gastric cancer patients have also been shown to have elevated serum VEGF levels that correlate with local tumor extent, disease stage and the presence of distant metastases. Importantly, after radical resection of the tumor, serum VEGF levels were significantly lower [108]. In a phase II study, only 1 of the 21 patients that were administered Sunitinib, had a partial response and 8 had stable Solid tumors, gastric cancer, CRC, thyroid cancer, renal cancer, NSCLC, gastrointestinal cancer, breast cancer, pancreatic cancer Solid tumors, liver cancer, CRC, gastrointestinal cancer Solid tumors, CRC, HM, glioblastoma, renal cancer, NSCLC, GIST, ovarian cancer, breast cancer, soft tissue sarcoma Solid tumors Glioblastoma, NSCLC Cancer Solid tumors Solid tumors Solid tumors, NSCLC Solid tumors Pancreatic cancer Cancer Malignant melanoma, urogenital cancer, gastric cancer, liver cancer, CRC, renal cancer, NSCLC, breast cancer, prostate cancer Solid tumors, gastric cancer, liver cancer, CRC, HM, renal cancer, NSCLC, breast cancer, GIST, prostate cancer, pancreatic cancer Solid tumors, gastric cancer Liver cancer, CRC, renal cancer, NSCLC, gastrointestinal cancer, breast cancer Solid tumors disease. Further trials involving Sunitinib and other standard chemotherapy treatments are being considered [109]. Scirrhous gastric cancer has the worst prognosis among all gastric cancer sub-types. It is associated with K-samII amplification which encodes the receptor for fibroblast growth factor (FGF-R2). Nakamura et al. [110] demonstrated that K-samII amplification was only present in human gastric cancer cell lines derived from scirrhous carcinoma. Ki23057, an inhibitor of K-samII/FGF-R2, has been shown to reduce the phosphorylation of K-samII/FGF-R2 and AKT, and promote apoptosis. Moreover, mice that were injected with scirrhous cancer cells had an increased survival rate when administered Ki23057 orally. 3.4. Liver cancer There are several types of liver cancer, including haemangioendothelioma, hepatocellular carcinoma (HCC), cholangiocarcinoma, haemangiosarcoma, hepatoblastoma, and bile duct cystadenocarcinoma. HCC is the third most common cause of cancer death worldwide. Over 80% of HCC cases are found in patients with liver cirrhosis, caused by chronic viral infection or alcohol consumption [111–113]. 992 G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 Fig. 1. Intervention of RTK signaling pathways. RTK signaling and resulting cellular responses can be modulated by using monoclonal antibodies and small molecule inhibitors targeting receptor tyrosine kinases and downstream kinases. Depicted drugs and according targets were adopted from Target Intelligence Service (TIS, www. targetintelligenceservice.com). Abbreviations: Cdc42: cell division control protein 42, ERK: extracellular signal-regulated kinase, mTOR: mammalian target of rapamycin, PI3K: phosphatidylinositol 3-kinase, EGF(R): epidermal growth factor (receptor), Grb2: growth factor receptor-bound protein 2, JNK: c-Jun N-terminal kinase, MEK/MKK: mitogenactivated protein kinase kinases, NRG: neuregulin, PDGF(R): platelet derived growth factor (receptor), SCF: stem cell factor, SOS: son of sevenless, TAK: TGFβ-activated kinase, TGF: transforming growth factor, VEGF(R): vascular endothelial growth factor (receptor). Since HCC is a highly vascularised tumor, angiogenesis plays an important role in the progression of the disease [114]. A positive correlation between over-expression of VEGF and microvessel density in HCCs has been reported [115]. VEGF has also been found to be an independent factor affecting metastasis and recurrence in HCC [116]. Several anti-angiogenic agents have been tested in patients with HCC, including Sorafenib and Sunitinib. Sorafenib, a multi-tyrosine kinase inhibitor (TKI), has recently been shown to increase overall survival in a multi-centre, doubleblind, placebo-controlled, phase III trial involving 602 patients with advanced HCC (SHARP trial). Analysis at the second interim showed that there was a significant difference in median overall survival between the Sorafenib and placebo group; patients treated with Sorafenib had a 2.8-month median survival benefit. In addition, 7 patients (2%) in the Sorafenib group achieved a partial response [117]. Another phase III trial showed that Sorafenib increased median overall survival by 2.3 months, concluding that Sorafenib is generally well-tolerated in patients with HCC [118]. Based on these results, Sorafenib was approved by the FDA for treatment of unresectable HCC (see also Table 3). Several phase II trials have evaluated the safety and efficacy of Sunitinib. Zhu et al. [119] found that of 34 patients enrolled, 1 patient had a partial response to 34 mg/day of Sunitinib, whereas 50% achieved stable disease. Importantly, Sunitinib was able to reduce tumor vessel leakiness while they reported that the response to this drug may depend on the balance between angiogenic and inflammatory pathways. Conversely, Faivre et al. [120] found that 50 mg/day of Sunitinib had pronounced toxicities. Although 1 patient had a partial response and 13 patients had stable disease over 3 months, there were 4 treatment-related deaths. Ito et al. [121] obtained HCC specimens from 100 patients, and found that 68% of them expressed EGFR. Moreover, this correlated with proliferating activity and intrahepatic metastasis. An early phase II trial of Erlotinib showed that 32% of patients were progression-free at 6 months, with a disease control rate of 59% [122]. Another phase II trial showed that there were no complete or partial responses to Erlotinib. However, 43% of patients did achieve stable disease, showing that Erlotinib has a modest benefit in the treatment of HCC [123]. Conversely, Gefitinib is not active as a single agent in advanced HCC [124]. 3.5. Colorectal cancer Cancer of the colon and rectum, also referred as colorectal cancer (CRC), is the second leading cause of death from cancer worldwide G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 [125]. For CRC, various signaling pathways of the molecular pathogenesis have been studied extensively. High throughput screening of sequences coding for kinase domains revealed 14 genes with somatic mutations in the tyrosine kinase family and 23 mutated genes all over the serine/threonine kinase family [126,127]. It is well described that carcinogenesis is the result of accumulated genetic alterations, whereas the primary mutation usually targets a single signal transduction pathway. For CRC, the WNT-signaling pathway plays a pivotal role. Aberrant activation of the canonical WNT-pathway can be found in almost all colorectal cancers [128]. CDK8 represents a gene that has been identified as modulator of β-catenin activity and colon cancer cell proliferation. CDK8 is necessary for β-catenin-driven transformation and for expression of β-catenin activated target genes. Suppression of CDK8 expression was shown to inhibit proliferation in colon cancer cells [129]. Loss of functional APC, as a further component of WNTsignaling, can be shown in 85% of all colorectal tumors [130]. When APC is mutated, colon cancer cells contain high levels of free β-catenin due to the lacking phosphorylation of β-catenin through the APC/ Axin/GSK3β/CK1 complex. De-stabilisation of free β-catenin is the key tumor suppressor function of unmutated APC [131,132]. Like in most neoplasms, the expression of EGFR is also upregulated in CRC (see Table 2). EGFR gene expression or up-regulation occurs in 60–80% of CRC cases while tumors expressing EGFR have poorer prognosis [133,134]. Trans-activation through prostaglandin E2 rapidly phosphorylates EGFR and triggers the ERK2-mitogenic signaling pathway in normal gastric epithelial and colon cancer cell lines. Inactivation of EGFR kinase through selective inhibitors significantly reduced PGE2-induced ERK2 activation and cell proliferation [135]. Downstream of EGFR signaling, KRAS can be activated by mutations resulting in the isolation of the pathway from the control of EGFR and therefore rendering EGFR inhibitors ineffective [136]. In about 40–50% of CRCs, activating mutations in the KRAS oncogene can be found [137,138]. KRAS is shown to be a starting point for several inter-connected pathways. KRAS activation initiates activation of the MAPK cascade whereas the MAP kinase RAF activates the dual specific kinases MEK1 and MEK2 (MAP kinase kinases 1 and 2). Downstream, ERK1 and ERK2 as well as JNK1 and JNK2 are activated resulting in further activation of multiple transcription factors with prominent roles in cell proliferation. Up-regulation of multi-drug resistance mediated machinery in tumors can also result from KRAS and MAPK cascade activation [139–141]. Inhibition of signaling through the MAPK cascade has been shown to inhibit tumor growth and to reduce the potential for metastasis in colon cancer [142]. In another KRAS initiated pathway, the serine/threonine kinase PI3K is activated which in turn activates AKT/PKB. Finally, this pathway leads to the activation of NF-κB, a potent survival promoting factor. Activated AKT also phosphorylates and inhibits the pro-apoptotic BCL-2 family member BAD and caspase-9 as well as GSK3β, the latter leading to the activation of β-catenin and transcriptional regulation [143,144]. During malignancy progression, colorectal adenomas lose the ability to respond to TGF-β, which can inhibit the growth rate of epithelial cells. Loss-of-function mutations leading to a frameshift in TGF-β type II receptors are quite common in colorectal tumor cell lines and lead to a proliferative advantage [145–147]. In tumors from members of HNPCC families frameshift mutations in the TGF-β type II receptor gene occur at high frequency [148]. The proto-oncogene c-Kit appears to be over-expressed and deregulated in CRC, but it is not clear if the protein is playing the same role in the carcinogenic process as it does in gastrointestinal stromal tumors (GIST) [149]. Growth, survival, migration and invasive potential of colon carcinoma cells can be favoured by c-Kit activation while blocking its activity results in inhibition of cellular proliferation and induction of apoptosis [150–152]. 993 In primary CRCs Aurora2 DNA amplifications resulting in a 1.5- to 10-fold increase in copy number are correlated with over-expression of the transcript in primary human colon carcinomas and various cultured colon tumor cell lines [303]. Finally, a truncating gain-of-function mutation of Src and lost expression of a catalytic subunit of PI3K can also contribute to the development of invasive colorectal malignancies [153,154]. The treatment of CRC mainly targets EGFR using two major inhibitor classes: monoclonal antibodies and TKIs. The human–mouse chimeric IgG1 monoclonal antibody Cetuximab (Erbitux®, Imclone) and the human IgG2 monoclonal antibody Panitumumab (Vectibix®, Abgenix) compete with the natural ligands (EGF and TGF-α) and bind to the extracellular domain of EGFR thereby blocking receptor activation and downstream receptor signaling (see Fig. 1). Patients with advanced CRC whose treatment with the topoisomerase I inhibitor Irinotecan (Camptosar®, Pfizer) and Cetuximab has failed to show synergistic activity. Therefore, Cetuximab has been shown to overcome Irinotecan resistance by abrogating drug efflux, restoring apoptosis or impairing DNA-repair activity [133,155]. In general, EGFR inhibition is likely to render cells more vulnerable to the effects of chemotherapy [156]. In 2004, the FDA approved Cetuximab for the treatment of EGFR-expressing, Irinotecan-refractory, metastatic CRC. However, a recent study showed that the therapeutic benefit of Cetuximab and Panitumumab is limited to patients with cancer bearing unmutated copies of the KRAS gene [157]. Consequently, in 2007 the European Medicines Agency (EMEA) has approved Panitumumab for the treatment of patients with wild-type KRAS tumors only. TKIs inhibiting EGFR family members are represented by Gefitinib, Lapatinib and Erlotinib. In combination with conventional chemotherapy, Gefitinib showed additional growth inhibitory effects [158,159]. Furthermore, in cell lines resistant to Cetuximab, both Gefitinib and Erlotinib restored sensitivity to Cetuximab [160]. Conversely, Lapatinib was evaluated as a monotherapy in a phase II study involving patients with metastatic CRC. Of these patients, 54% expressed EGFR and 44% expressed HER2. Although Lapatinib was well tolerated, only 5 patients experienced clinical benefit with stable disease, suggesting that it has limited activity as a single agent in the treatment of metastatic CRC [161]. These data suggest that TKIs are able to further modulate intracellular signaling which is not fully blocked by treatment with anti-EGFR antibodies [162]. Future agents targeting EGFR, among them small molecule inhibitors like AEE 788, [163], HKI-272 (Neratinib) [164] and EKB569 [165] are currently under investigation in clinical trials (see also Table 3). Moreover, combinations of targeted agents and potent single-target agents in combination with conventional chemotherapy will be investigated in future studies aiming to result in greater growth inhibitory activity [162,166]. 3.6. Pancreatic cancer Pancreatic cancer is the fourth leading cause of cancer-related death although its incidence is very low (approximately 10 in 10,000 people). Patients have a very poor prognosis and less than 5% have a greater than 5 years survival rate [167] as a result of resistance to common therapies including chemotherapy, radiotherapy and immunotherapy. About 95% of pancreatic tumors are adenocarcinomas, while the rest are tumors of the exocrine pancreas like acinar cell cancers, and pancreatic neuroendocrine tumors [168]. Several protein kinases are involved in the development and progression of pancreatic cancer and therefore represent good targets for tumor therapies [169,170]. The PI3K/AKT survival pathway, which is activated by survival signals like growth factors plays an important role in pancreatic cancer cells and is activated in about 60% of all pancreatic adenocarcinomas [171–173]. EGFR is over-expressed in pancreatic 994 G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 tumors and is connected to a very unfavorable prognosis and survival rate [174,175]. After EGFR activation and dimerisation with other members of the ErbB receptor family, the tyrosine residues are phosphorylated and the activity of the kinase is up-regulated. Consequently, signals are mediated via the RAS-RAF-MAPK and the PI3K/AKT pathways [176]. mTOR, a serine/threonine kinase which plays an important role in cell proliferation and survival, is activated downstream of the PI3K/AKT pathway, and also over-expressed in pancreatic tumors [177,178]. HER2 protein kinase, a member of the ErbB receptor family, is over-expressed in pancreatic cancer as well [175]. Moreover, the trans-membrane receptor tyrosine kinase EphA2 is up-regulated in pancreatic cancer and is associated with poor prognosis [179,180]. Small molecule inhibitors as well as monoclonal antibodies are both employed in the treatment of pancreatic cancer. Monoclonal antibodies can inhibit ligand binding to EGFR thereby blocking downstream signal transduction. Several monoclonal antibodies are under investigation for use either alone or in combination with other conventional chemotherapies. In vitro (pancreatic cell lines) and in vivo (orthotopic nude mice) studies revealed that the monoclonal antibody Cetuximab leads to decreased EGFR phosphorylation, proliferation and angiogenesis and an increase in apoptosis [181–183]. Kullmann et al. found that metastatic pancreatic cancer therapy with a combination of Gemcitabine and Cetuximab is well tolerated, but does not increase response or survival of patients [184]. The TKI Erlotinib in combination with Gemcitabine gave promising results in a phase III trial, leading to an overall survival rate for pancreatic cancer [185]. Furthermore, treatment of 28 metastatic pancreatic cancer patients, who did not respond to therapy with Gemcitabine, with a combination of Erlotinib and Cepacitabine, resulted in 57% of stable disease with a median survival of 6.7 months [186]. The involvement of CK1 family members' deregulation in the control of various cellular processes has been described for several tumor entities [23,24], including adenocarcinomas of the pancreas [187]. Inhibition of CK1δ/ε by small molecule inhibitors has been shown to reduce induced tumor growth in severe combined immunodeficiency disease mice to a similar extend as Gemcitabine. The development of high specific CK1 isoform specific inhibitors [188] will increase the potential of CK1 specific inhibitors for use in new therapeutic concepts in the treatment of multi-drug resistance in pancreatic tumors. 3.7. Adrenocortical carcinoma With an incidence of only 0.5–2 cases per million every year, adrenocortical carcinoma (ACC) is a rare disease. ACC has a bimodal age incidence, with peaks in the first and fourth decades of life. Tumors are characterized as functional when the hormonal secretions lead to clinical consequences including Cushing's syndrome, virilization syndrome, feminization syndrome and mixed Cushing–virilizing syndrome [189,190]. The most frequent genetic alteration in ACC is the over-expression of IGF (see Table 2) [191–193]. An up-regulation of IGF2 has been observed in 91% of ACCs compared to the mean of the adrenocortical adenoma/normal adrenal cortex cohort. In addition, a differential expression of Aurora2 in ACC has also been reported [193]. Another study showed that there were two clusters of genes which differentiated adrenocortical carcinomas from adenomas, and therefore possible markers of malignancy. Patients with tumors that had a high expression of the IGF2 cluster (including the IGF2 gene) and low expression of the steroidogenesis cluster, also had a high probability of metastatic recurrence [192]. A preclinical study to test the effects of IGF-1R antagonists on ACC revealed 2 different IGF-1R antagonists (IMC-A12 and NVP-AEW541) that caused dose-dependent growth inhibition in ACC cell lines [194]. Furthermore, growth inhibition was enhanced when the antagonists were combined with Mitotane, the first-line drug used in patients with ACC, suggesting a crucial role of IGF signaling in this cancer. EGFR over-expression has been identified in the majority of ACC cases [195,196]. Fassnacht et al. [195] found that EGFR was expressed in 78% of ACCs, but did not correlate with clinical outcome. However, EGFR specific SMIs have proved to be clinically ineffective. None of the patients with ACC achieved partial response or stable disease after Gefitinib treatment [197]. Similarly, Quinkler et al. [198] found that Erlotinib plus Gemcitabine had very limited activity; at the first staging, only 1 out of 10 patients had a minor response, whereas progressive disease was found in 8 patients. After treatment initiation, 90% of the patients died after a median of 5.5 months. 3.8. Kidney cancer In 2007 approximately 51,000 people were diagnosed with renal cell carcinoma (RCC) in the USA [125,185]. VEGF plays an important role in the development of renal cell carcinoma and is over-expressed in the tumor tissue of a majority of patients with clear-cell RCC [199,200]. Inactivation of the Hippel– Lindau (VHL) tumor suppressor gene results in an over-expression of VEGF leading to the activation of the PI3K/AKT [201,202], the RAF/ MEK/ERK and the p38MAPK signaling pathways [199]. Several isoforms of PKC are also involved in the development and progression of RCC. Upstream signals, like VEGF, can activate PKCs, which in turn can activate downstream signals such as the RAF-1/ MAPK signaling pathway [203], which is responsible for the transduction of signals through the cytoplasm. As a result, many genes participating in cell proliferation and invasion are being overexpressed. Several therapeutic strategies were designed for targeting the VEGF pathway. Bevacizumab, a human monoclonal antibody against VEGF [204] blocking all biological active isoforms of VEGF, showed only minimal adverse effects in phase II clinical studies [205]. Several phases II and III clinical trials revealed that patients with RCC have a clinical benefit after treatment with the VEGFR2 and PDGFR-β targeting small molecule inhibitors Sunitinib and Sorafenib [206]. However, their long term effects on tumor shrinkage or overall survival remains unclear. Based on the data so far, it seems that inhibiting the VEGF pathway alone in patients with RCC may be insufficient. Therefore, a combination of multiple inhibitors involved in relevant pathways in the pathogenesis of RCC is considered essential. 3.9. Bladder cancer According to Wallerand et al. [207] bladder cancer is the seventh most common cancer worldwide. Smoking is considered to be the major risk factor for bladder cancer. Smokers have high nicotine concentration in their bloodstream and urine, which send signals through nicotinic acetylcholine receptors (nAChRs) in the brain [208]. Studies have shown that nicotine promotes cancer cell growth by transactivating β-adenoreceptor and EGFR [209]. The major signaling pathways that are involved in nicotine induced cell proliferation are ERK1/2 and STAT 3. According to Chen et al. [208] when these two pathways are activated by nAChR and β-adenoreceptor, nicotine exposure disrupts the cell cycle progression by increasing S phase, and elevating expression of Cyclin-D1, Cyclin-A, PCNA and phosphorylation of retinoblastoma protein. EGFR is over-expressed up to 48% in bladder cancer (Table 2) [207]. In vivo studies have demonstrated that a chimeric monoclonal antibody known as Cetuximab can inhibit EGFR efficiently in combination with Paclitaxel. It has also been shown to have inhibitory effects in metastatic bladder cancer [210]. While numerous agents such as Gefitinib and Erlotinib demonstrated reduced efficacy in G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 bladder cancer, Sorafenib, an SMI, is currently under phase II investigation for advanced and metastatic bladder cancer. Sorafenib mainly targets VEGF and PDGF receptors and has already been approved by the FDA for use in advanced kidney cancer [207]. Another target that has been identified in bladder cancer is the PI3K/AKT pathway. Activation of PI3K in bladder cancer, initiates PIP3 which in turn phosphorylates and activates AKT. This leads to tumor cell mobility and invasion, and to apoptotic and therapeutic resistance. Rapamycin can specifically inhibit alteration of the PI3K/ AKT pathway by directly binding to FKB protein 12, which in turn blocks the mTOR pathway [207], representing one of the possible targets that is still being clinically evaluated for various human solid tumors including bladder cancer. 3.10. Endometrial, cervical and ovarian cancer There are two major types of endometrial cancers, termed type 1 and type 2. Type 1 endometrial cancer is usually associated with unrestricted exposure of estrogen and the main genetic alterations are micro-satellite instability and mutations in PTEN, KRAS, and β-catenin [211]. Every year in the United States, 70–80% of women diagnosed with endometrial cancer belong to type 1 [212]. The IGF-1 pathway has been shown to play an important role in the development of endometrial cancer. A decrease in the level of PTEN initiated by AKT leads to activation of IGF-1, which in turn mediates estrogen stimulation by inducing cell proliferation [211]. Type 2 endometrial carcinoma is common among postmenopausal women accounting for 10–20% [211]. In approximately 20% of type 2 cases an over-expression of HER2/neu has been observed [213]. In this Type 2, various kinases are constitutively activated, leading to mitogenic cell signaling and cell proliferation [214]. As AKT is constitutively activated due to deletion of PTEN, it activates mTOR, a common target in endometrial cancer, which can be inhibited by Rapamycin [211]. Thus far, three main Rapamycin analogues exist, which are being clinically tested as anticancer agents for solid tumors including endometrial cancer: i) Temisorilimus, ii) Deforolimus and iii) Everolimus (see also Fig. 1). Due to limited success and poor prognosis for patients with chemotherapeutic treatment for cervical cancer, interest in treatments with target therapeutics has increased [215]. VEGF represents a main therapeutic target in cervical cancer. Elevated intra-tumoral protein levels of VEGF have been reported to increase in cervical cancer, and to be responsible for lymph node metastasis [216]. Inhibitors such as Gefitinib, Erlotinib and Lapatinib have been investigated in phase II clinical trials. While Gefitinib shows poor efficacy, Erlotinib is being evaluated as a monotherapy and along with Cisplatin and radiotherapy in locally advanced squamous cell cervical carcinoma. Lapatinib, a dual TKI of HER1 and HER2 is also being investigated in studies as a monotherapy and in combination with Pazopanib, a multi-targeted TKI. Results of these trials are still anticipated [215]. Further ongoing phases I and II clinical trials include co-treatment with Sorapanib and Pazopanib. Finally, combinations of Pazopanib with Lapatinib are being tested in patients with metastatic cervical cancer. Ovarian cancer is the second most common gynecological cancer in the western world [217]. However, since no specific mutations or gene amplifications have been found for the progression of ovarian cancer, designing specific therapeutic agents has been proven a difficult task [217]. Therefore, molecular targeted agents are combined with cytotoxic treatment to give a successful result. As EGFR is over-expressed in 30–70% cases of ovarian cancer, it remains the main focus of drug targeting [217]. Inhibitors such as Gefitinib, Erlotinib, Cetuximab and Matuzumab are being clinically evaluated in different phases. 995 VEGF has also been revealed to mediate malignant progression in ovarian cancer [218]. Bevacizumab, a monoclonal antibody and Sorafenib, a small molecule inhibitor and decoy receptors represent two main trial agents currently under investigation in order to inhibit VEGFR [217]. Other receptor tyrosine kinases that are involved in tumor cell growth, angiogenesis and vasculogenesis of ovarian cancer include c-Kit and PDGFR. These two receptor tyrosine kinases are overexpressed in 70–73% of ovarian cancer [217,219]. Imatinib has been successfully used against these kinases, demonstrating positive results in combination with cytotoxic agents [220]. Many other potential targets such as Src family, JAK/STAT pathway, Ras/Raf/MEK/MAPK pathway, PI3K/AKT/mTOR pathway, PKC family, Aurora kinase family and proteases are still under investigation. While various drugs are being clinically evaluated and studied thoroughly, the combination of Carboplatin and Paclitaxel is the current treatment for advanced ovarian cancer [217]. 3.11. Prostate cancer Prostate cancer is the most common cancer among men in Europe and the United States [221,222] and the second leading cause of death after lung cancer [223]. As mentioned earlier in this review, expression of EGFR has been detected in most types of cancers, including prostate cancer. It is well established that EGFR/HER2 signal transduction pathway downregulation leads to tumor pathogenesis, growth, and metastasis [224]. Festuccia et al. [225] demonstrated that autocrine secretion of EGFR ligands is associated with androgen independence in prostate cancer cell lines. In addition, EGFR dimerization with HER2 revealed involvement in tumor growth at castrate hormonal level, thereby suggesting that inhibition of HER2 dimerization could be an important therapeutic target in castration resistant prostate cancer. According to Malik et al., [226], Erlotinib is an effective and specific inhibitor of HER1/EGFR tyrosine kinase. It has also been shown to inhibit HER2 kinase and downstream signaling in cells that do not express EGFR. However, it has been reported that the efficacy of Erlotinib depends on the ratio of EGFR/HER2, indicating poor effects when levels of HER2 are increased while EGFR levels are low [225]. PTEN is a well known suppressor of PI3K/AKT pathway; mutation or loss of PTEN could lead to elevated activation of the PI3K/AKT cascade [227]. It has been reported that in prostatic lesions there is loss of chromosome 10q, where PTEN is located. Sarker et al. [228] recently verified that activation of PI3K can increase the phosphorylation of AKT due to loss of PTEN. The activated AKT translocates to the cytoplasm and nucleus triggering numerous downstream targets, including activation of mTOR that initiates cell survival, proliferation, cell cycle progression growth, migration, and angiogenesis [228]. Phase 1 trial of PI3K inhibitors that are currently evaluated include XL147 (Exelixis), BEZ235 (Novartis), and GDC-0941 (Genentech) (see also Table 3). Preliminary studies have shown that these drugs are well tolerated and may minimize toxicity [229]. Perifosine, a novel inhibitor of AKT, has entered phase II clinical trials, but has shown to have minor effects [228]. This is due to mutation of PTEN which limits the therapy induced apoptosis [227,230]. Regarding mTOR, dual mTORC1/mTORC2 ATP competitive kinase inhibitors are presently being clinically tested, demonstrating however signs of toxicity [228]. Moreover, dysregulation of CK2 has been reported to be associated with other cascades of events leading to increased oncogenesis in prostate cancer [231]. Use of the specific chemical inhibitor 4, 5, 6, 7tetrabromobenzotriazole (TBB) induced apoptosis in prostate cancer cells. However, this inhibitor is still being investigated [232,233]. Another tyrosine kinase that is associated with prostate tumor is Src, which plays a vital role in both, health and disease, especially bone turnover. Src, androgen receptor (AR) and estradiol receptor complex signaling have been shown to generate prostate cancer cell 996 G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 proliferation in vitro [234]. Moreover, it has been reported that Src regulates cell migration of bone-derived metastatic castration resistant prostate cancer cells [235], turning Src into a promising therapeutic target. So far, there are two clinical agents in development that have been introduced for castration resistant prostate cancer: i) AZD0530, an orally active Src/Abl phase I trial inhibitor demonstrated dose dependent inhibition of Src, proliferation and migration in numerous prostate cancer cell lines including those derived from bone metastatic castration resistant tumors [234]. In vivo studies in mouse models have shown that AZD0530 completely inhibited metastasis and hindered osteolytic lesion in castration resistantmetastasis [234]. At present, AZD0350 is being evaluated in a phase II trial in patients with prostate cancer metastasis [234]. ii) Dasatinib, a small-molecule TKI, has been shown to block numerous receptor and non-receptor tyrosine kinases [236]. Preclinical studies revealed that Dasatinib inhibits several kinase activities and also inhibited downstream signaling in androgen dependent and independent human prostate cancer cells [237]. Another report suggests that Dasatinib inhibits growth, lymph node metastasis, and osteoclast mediated bone resorption in vivo [234]. Further studies demonstrated blockade of migration and invasion and induced apoptosis in bone sarcoma cell culture [238]. Dasatinib has been approved for treating all phases of chronic myelogenous leukaemia and Philadelphia chromosome-acute lymphoblastic leukaemia. However, at present it is evaluated in numerous solid tumors including prostate cancer [234]. 3.12. Breast cancer The most common kinase associated with breast cancer is HER2/ neu, which is over-expressed in about 20% of all breast tumors [239]. After dimerisation of HER2 and HER3, the PI3K survival pathway is activated, which down-regulates the estrogen receptor (ER) resulting in a lower sensitivity to hormonal therapies [240]. Furthermore, to avoid apoptosis, HER2/neu is able to increase the amount of the antiapoptotic protein survivin [241]. Dimerisation of HER2/HER3 leads to amplification of c-myc. Subsequently, the kinase inhibitor p27KIP is degraded and an increased proliferation of HER2/neu positive cells can be detected [242]. Besides the PI3K survival pathway, HER2 can also activate the MAPK pathway. Recently, Montero et al. [243] showed that one kinase in this pathway, ERK5 kinase, was over-expressed in 20% of 84 breast cancer patients and this was associated with a decrease in freesurvival time [243]. Inhibition of ERK5 in cell culture revealed a decrease of cancer cell proliferation sensitizing cells to anti-HER2 therapeutics. Based on these results, ERK5 may represent a future therapeutic target [243]. In addition to HER2/neu, c-Abl plays an important role in the tumorigenesis of breast cancer [244–246]. C-Abl is involved in three different pathways and can be activated by EGFR, IGF-1R and Src [244,246]. After EGF stimulation, c-Abl is activated by binding to EGFR; EGFR-independent activation of c-Abl can also occur through activated Src kinase [245]. Src, a non-receptor tyrosine kinase, plays an important role in the development of breast cancer. Ligand activation of cell surface receptors like EGFR or cytoplasmic proteins like focal adhesion kinase (FAK) are able to activate the Src kinase [247]. Autophosphorylation (Y419) and dephosphorylation (Y530) events also contribute to activation of Src [248]. Trastuzumab, a monoclonal antibody, and Lapatinib, a smallmolecule inhibitor, play an important role in the treatment of HER2/ neu positive mammary carcinomas. Lapatinib inhibits kinase activity of both, HER1 and HER2. However, to date promising therapeutic effects could only be achieved in tumors over-expressing HER2 [249–251] resulting in apoptosis of tumor cells by down-regulation of survivin and inhibition of downstream signaling pathways (MAPK and PI3K/AKT pathways) of HER2 [250–252]. Lapatinib is already in a clinical phase II trial for application in brain metastasis and after promising results in 2007 it gained FDA approval [253,254]. Trastuzumab acts through binding to the extracellular domain of HER2 leading to inactivation of its intracellular tyrosine kinase and subsequently to inhibition of the resulting signaling cascade [255]. Binding of Trastuzumab to the HER2 receptor results in prevention of receptor heterodimerisation (see Fig. 1), an increased endocytoxic destruction of the receptor and an immune activation leading to the inhibition of tumor cell growth in vitro and in vivo [256–258]. Trastuzumab is used either as a monotherapy or in combination with other therapies. First clinical phase II studies, using Trastuzumab as a monotherapy in patients with previously pre-treated metastatic breast cancer, revealed that only 12% of the patients showed a positive response to this therapy [259,260]. In a further study, a 35% response rate could be achieved using previously untreated patients [261]. The application of Trastuzumab in combination with different chemotherapeutics has been reported in several different clinical trials with patients with metastatic breast cancer. These studies revealed an increased time to disease progression. Moreover, these patients had a lower death rate at one year, a longer median survival and a 20% reduction in the risk of death, compared to patients who received chemotherapeutics alone [262,263]. Furthermore, four large randomized studies achieved promising results from the addition of Trastuzumab to adjuvant and neo-adjuvant therapies. These adjuvant therapies in combination with Paclitaxel revealed a significant increase in disease-free survival and overall survival, compared to treatment with chemotherapy alone [264–266]. The Src kinase also represents a therapeutical target for breast cancer and there are now several Src inhibitors in clinical development. The small-molecule inhibitor Dasatinib inhibits several kinases of the Src family among them c-KIT, PDGFR and Bcr-Abl [236]. Preclinical and clinical phase I and II studies revealed promising results, either using Dasatinib alone or in combination with Capecitabine [267]. Furthermore, Bosutinib (SKI-606), applied to inhibit a Src-dependent tyrosine phosphorylation, resulted in a dose-dependent inhibition of cell proliferation and invasion [268]. This inhibitor is currently in clinical elvaluation. A third inhibitor of Src and Abl kinases is AZD0530, generated by AstraZeneca [269]. Phase I studies revealed an inhibition of Src phosphorylation and therefore a reduced kinase activity in MCF-7 cells [270]. AZD0530 is also being tested in ongoing clinical phase II studies in patients with metastatic breast cancer. 3.13. Sarcomas Sarcomas are a heterogeneous group of rare malignancies arising from mesoderm-derived connective tissues. There are more than 50 different histological subtypes, which differ in their clinical presentation and disease course [271,272]. This part of the review will concentrate on the types of sarcomas associated with expression of c-Kit, PDGFR, EGFR and VEGF, although other markers have been identified. 3.13.1. GIST In GIST somatic gain-of-function mutations in the c-kit gene were identified resulting in the constitutive activation of c-KIT receptor tyrosine kinase. Activation of c-Kit by its ligand SCF (stem cell factor) plays an important role in cellular transformation and differentiation [273–275]. In GIST lacking c-kit mutations, activating mutations in the PDGFR-α gene have been detected. 80–90% of mutations are localized in the c-kit and 5–10% in the PDGFR-α gene while up to 5% are wild type GIST [276]. The reported c-kit and PDGFR-α mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs [277]. Data relating to the prognostic value of the mutational status are still under debate. However, the role of mutated c-KIT is not completely understood but reports show that c-Kit activity may induce cell proliferation while further tumor progression seems to be associated with a decrease in c-KIT expression [152]. G. Giamas et al. / Cellular Signalling 22 (2010) 984–1002 As the standard first-line treatment in advanced disease SMIs like Imatinib targeting c-KIT and PDGFR are used. Inhibiton of PDGFR has been shown to reduce intestinal hypertension and to increase transcapillary transport in tumors thus enhancing antitumor effects of conventional chemotherapy [278,279]. In GIST patients with acquired resistance to Imatinib the PDGFR inhibitor Sunitinib malate (Sutent®, Pfizer) shows direct anti-tumor activity [280]. However, surgery remains the only curative treatment for GIST. In patients who initially responded to Imatinib, secondary resistance often occurs due to a second mutation in the c-Kit gene resulting in tumor progression at a median of 18–24 months [281–285]. At present, the use of Imatinib in adjuvant treatment is heavily discussed since special parameters are required to select patients within the high risk group which are suitable for adjuvant therapy concepts [286]. 3.13.2. Other sarcomas 3.13.2.1. c-KIT. c-KIT also has a role in the pathogenesis of other sarcomas. In a proportion of synovial sarcomas, osteosarcomas and Ewing sarcomas (ES), there is strong, diffuse staining for c-KIT [287]. Scotlandi et al. [288] found that 31% of tumor biopsies obtained from patients with ES expressed c-Kit. However, there was no significant correlation between the expression level and the clinical outcome. There was limited growth inhibition in ES cell lines treated with Imatinib, which was greater when Imatinib and Doxorubicin were combined. In a phase II study involving 24 patients with ES, only 1 had a partial response to Imatinib treatment, showing that it has limited activity as a single agent in ES [289]. Moreover, a recently published phase II study evaluated the effect of Imatinib in 10 different types of sarcomas. However, from the 185 patients that were treated and assessed for response, only one complete and three partial responses were achieved, concluding that Imatinib is not an active agent in these subtypes of sarcoma [290]. 3.13.2.2. PDGFR. Imatinib has also been evaluated in a clinical trial involving patients with AIDS-related cutaneous Kaposi's sarcoma (KS). With regards to tumor measurement, 5 of 10 patients achieved partial response. Biopsies taken 4 weeks post-treatment showed histological regression in 4 of 6 patients. Furthermore, immunohistochemistry confirmed reduced phosphorylation of PDGFR and ERK, which correlated with regression. There was no change in the staining for phospho-c-Kit after treatment [291]. Kubo et al. [292] reported that PDGF-AA (80%), PDGFR-α (80%), PDGF-BB (75%) and PDGFR-β (86%) were expressed in a large majority of osteosarcomas. Imatinib treatment inhibited AKT phosphorylation, but did not affect the constitutive activation of MAPK, concluding that Imatinib has no role as a single agent in the treatment of osteosarcomas. Dermatofibrosarcoma protuberans (DFSP) is associated with the ectopic production of PDGF-BB as a result of chromosome translocation [293]. Rubin et al. [294] demonstrated that Imatinib treatment can reduce the volume of the tumor by 75% in a patient with DFSP. Another phase II study showed that Imatinib is active in patients with localized and metastatic DFSP, of which 50% achieved a complete response [295]. 3.13.2.3. EGFR. A study involving 281 patients revealed that 60% of soft tissue sarcomas are EGFR-positive [296]. In particular, 76% of synovial sarcomas showed positive staining [296]. In addition, another study demonstrated that 55% of synovial sarcoma specimens expressed EGFR [297]. A phase II study of Gefitinib showed that although 21% of patients with synovial sarcoma achieved stable disease, 70% suffered disease progression [298]. 3.13.2.4. VEGFR. A phase II trial of Semaxanib, a small molecule inhibitor of VEGFR2 and c-Kit, failed to produce any objective tumor 997 responses in patients with soft tissue sarcoma. Furthermore, there was no reduction in the phosphorylation of VEGFR [299]. A phase II trial of Sorafenib recruited patients with recurrent or metastatic sarcoma, demonstrating an activity only against angiosarcomas [300]. Pazopanib, an angiogenesis inhibitor, which inhibits VEGFR, PDGFR and c-KIT, was used in a recent phase II study, where 9 patients achieved partial response (1 with leiomyosarcoma, 5 with synovial sarcoma and 3 with other types). A phase III study of Pazopanib is now in progress (see Table 3) [301]. 4. Conclusion/future prospects Kinases as molecular targets for cancer drug development are of potential interest. So far, various kinase inhibitors have been tested in clinical trials resulting in great survival benefit for patients for whom no effective therapy was available. However, the molecular complexities of solid tumors impose for the development and optimization of kinase inhibitors in order to be used in single and/or combined therapies. In this aspect, analysis of biological homogenous groups of tumors regarding their response to kinase inhibitors, alone or in combination with other therapeutics, will be a major goal in the establishment of more ‘personalized’ therapies. Therefore, understanding the pathogenesis of the diverse solid tumors is very important in order to classify them on the molecular level. In addition, use of modern and advanced technologies will help us identify novel kinases that can be used as targets for cancer treatment. Furthermore, experimental animal models and cancer stem cell lines can be used as powerful tools to test these new drugs. Finally, properly designed clinical trials will improve their clinical effectiveness in single and combined treatment therapies. Acknowledgements We are grateful to Annette Blatz and Colin Wickenden for their support and help with editing the manuscript. 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