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DRUG DEVELOPMENT RESEARCH 62:254–272 (2004)

DDR
Research Overview
Pharmacogenomics of the P53 Tumor Suppressor and Its
Role in Cancer Chemoresistance
Suxing Liu,n W. Robert Bishop, Bimal Dasmahapatra, and Yaolin Wang
Biological Research-Oncology, Schering-Plough Research Institute, Kenilworth, New Jersey

Strategy, Management and Health Policy

Enabling Preclinical Development Clinical Development


Technology, Preclinical Toxicology, Formulation Phases I-III Postmarketing
Genomics, Research Drug Delivery, Regulatory, Quality, Phase IV
Proteomics Pharmacokinetics Manufacturing

ABSTRACT Drug resistance remains a key obstacle to successful cancer treatment. The implementa-
tion of pharmacogenomics is widely proclaimed as a route to revolutionize the face of cancer therapy.
Here we discuss the pharmacogenomics of the p53 tumor suppressor and its role in cancer
chemosensitivity. It has been proposed that p53 has a profound impact on the response to chemotherapy
and participates in development of drug resistance in tumor cells. This is based on the dual role of p53 as a
guardian of genome integrity and as a key mediator of apoptosis. Alterations of the p53 gene occur in
approximately 50% of human cancer, and human tumor cells retaining wild-type p53 often have
epigenetic defects in the p53 pathway. Extensive mechanistic studies of drug action suggest that virtually
all cancer cells have a dysfunctional p53 system (including p53 and its associated proteins, both upstream
regulators and downstream targets). Various experimental approaches to correct the p53 pathway defects
in tumor cells are discussed. Many studies have correlated p53 status with prognosis and therapy response
in tumors. However, the impact of p53 status on drug resistance of tumors is still controversial. The impact
of p53 on chemosensitivity is complex and multifactorial, depending on the genotypic/phenotypic context
of the cell. Recent technological achievements have fostered a renewed interest in pharmacogenomics of
p53 and its association with drug response. These include high-throughput tissue microarray analysis of
p53 protein expression, single nucleotide polymorphism genotyping of the p53 gene, and gene expression
profiling to identify the gene signature of p53-associated chemoresistance. Knowledge from pharmaco-
genomic studies will provide an opportunity for improvements in drug efficacy through effective
stratification of patients, and early identification of those individuals most likely to respond effectively to a
specific therapy. Drug Dev. Res. 62:254–272, 2004. c 2004 Wiley-Liss, Inc.

Key words: p53 tumor suppressor, pharmacogenomics, mutation, chemoresistance, chemosensitivity

INTRODUCTION therapeutic agents. The response depends on the


The variability in response to cancer therapy is a cellular genotype and, especially, on the integrity of
major problem in clinical practice and cancer drug the response pathways downstream of the drug–target
development. A significant proportion of cancer interaction. Determination of the status and function of
patients either fail to respond satisfactorily or react specific genes and molecular pathways should be useful
adversely to therapy. Multiple factors likely contribute n
Correspondence to: Suxing Liu, Ph.D., Tumor Biology
to these interindividual differences. One determinant Department, Schering-Plough Research Institute, 2015 Galloping
of intrinsic drug resistance occurs upstream of drug– Hill Road, K-15-4 (4600), Kenilworth, NJ 07033-1300.
target interaction (e.g., drug metabolism or drug E-mail: suxing.liu@spcorp.com
transport mechanisms). It is now clear that genetic Published online in Wiley Interscience (www.interscience.
factors also contribute to the response to antitumor wiley.com) DOI: 10.1002/ddr.10362


c 2004 Wiley-Liss, Inc.
P53 TUMOR SUPPRESSOR AND CANCER CHEMORESISTANCE 255

in the prediction of treatment sensitivity or resistance acts as a sequence-specific transcription regulator of


[Wang and Beck, 1998]. many genes involved in control of cell cycle, apoptosis,
It is generally accepted that p53 plays an differentiation and development, senescence, DNA
important role as ‘‘guardian of the genome.’’ p53 is a repair and replication, and maintenance of genomic
transcription factor and a key regulator of cell stability [Vogelstein and Levine, 2000]. p53 protein
proliferation, differentiation, DNA repair, and apopto- consists of four domains (Fig. 1): a transactivation
sis [Vogelstein and Levine, 2000]. The p53 tumor domain, a DNA binding domain, a tetramerization
suppressor gene is the most frequent target of genetic domain, and a C-terminal regulatory domain [Soma-
alterations in human cancer [Soussi, 2000]. The sundaram and El-Deiry, 2000]. The DNA binding
efficacy of many chemotherapeutic drugs depends on domain harbors majority of mutations including all of
their ability to trigger apoptosis in tumor cells. the hotspots residues [Cho et al., 1994]. There are
Accordingly, loss of wild-type p53 function in tumors more than 18,500 somatic mutations and 250 germline
could lead to increased chemoresistance as conse- mutations reported to date in the p53 database [Beroud
quence of abrogation of p53-dependent apoptosis. In and Soussi, 2003; Olivier et al., 2002]. The majority
this review, we focus on pharmacogenomics of p53 and (E88%) of p53 mutations are missense, resulting in a
its role in cancer chemosensitivity. more stable protein that accumulates in cancer cells.
The high frequency of missense mutations, as opposed
P53 MUTATIONS AND TUMOR PROGNOSIS to truncations or deletions, distinguishes p53 from
other tumor suppressors (e.g., the retinoblastoma
Mutation and Variations in the p53 Gene protein) and suggests that there is a positive selection
There is growing evidence that inactivation of the for mutant p53. The fact that the mutant protein
p53 pathway occurs in almost all tumors. This leads to accumulates in cancer cells and is often retained in
uncontrolled cell growth, genomic instability in re- distant metastasis suggests that mutation results in
sponse to various stresses including DNA damage, and more than a loss of function. Indeed, some mutations
ultimately to cancer. Mutational inactivation of the p53 of p53 exhibit a gain-of-function phenotype that
gene is the most common alteration in human cancer, promotes cell growth and tumorigenicity [Cadwell
and p53 mutation is associated with 50% of all human and Zambetti, 2001; Harvey et al., 1995].
cancers [Soussi and Beroud, 2001]. In the remaining p53 mutations are found in almost every type of
cancers, p53 function is indirectly altered either due to human cancer. Malignancies with mutation frequencies
its ubiquitination and degradation initiated by over- greater than 50% include lung, colon, bladder, skin,
expressed Hdm2 protein, inactivation of p19ARF (e.g., and head/neck. Intermediate mutation frequencies
sarcoma), interaction with viral protein (e.g., cervical (20–45%) are found in lymphomas, breast, liver, brain,
cancer), or by nuclear exclusion (e.g., neuroblastoma). and prostate cancers [Hainaut and Hollstein, 2000].
In many cancers containing a mutant p53 allele, loss of Malignancies such as leukemia and testicular cancer,
heterozygosity occurs, leading to loss of the wild-type which are more sensitive to chemotherapy and
allele. Inherited loss of heterozygosity is also seen in radiation therapy, have lower mutation frequencies
cancer-prone Li-Fraumeni patients. (5–10%). The timing of occurrence of the mutation
The p53 protein is constitutively expressed in during cancer progression is extremely variable from
almost all cell types. It is a short-lived protein and one cancer to another. In cancers such as those of the
appears to be latent in normal cells. In response to colon, prostate, and breast, p53 mutations and loss of
various cellular stresses, p53 level is increased and it heterozygosity preferentially occur at a relatively late

Fig. 1. Functional domains of the tumor suppressor p53. The p53 molecule is illustrated with boundaries of four functional domains as well as
mutational hotspots in human cancer.
256 LIU ET AL.

stage in their histopathological development [Fearon heterogeneity of the mutagenic processes that inacti-
and Vogelstein, 1990]. In contrast, p53 mutations occur vate p53. The vast majority of the mutated codons are
at an early stage in many types of cancer that are at common sites that are likely to result in dysfunctional
directly caused by exogenous carcinogens. This is the p53. The six hotspot codonsF175, 245, 248, 249, 273,
case for lung cancers in smokers, nonmelanoma skin and 282Frepresent more than 30% of all oncogenic
cancers after ultraviolet (UV) exposure, and in most mutations. Mutation of these residues inactivates p53
forms of oesophageal cancers. p53 mutations in these either by abrogating essential DNA contacts or
cancers are often detectable in hyperplastic and destabilizing the binding surface. The p53 DNA
dysplastic lesions, as well as in apparently normal binding domain is exceptionally flexible, and conforma-
tissue surrounding the tumor [Montesano et al., 1997]. tional flexibility is key to its essential biological roles in
The pattern of p53 mutations is dominated by tumor suppression [Cho et al., 1994; Lane and Hupp,
base transitions, 51% are G:C to A:T, and 60% of these 2003; Yakovleva et al., 2002].
affect a CpG dinucleotide. Ninety percent of CpG Mutations of p53 other than missense are
transitions are at one of six hotspot codons: 175, 213, complex in nature and include short insertions and
245, 248, 273, and 282. CpG transitions are found at deletions or frame-shifts resulting in no accumulation
high frequency in cancers of the colon, stomach, brain, of protein. Survey of the IARC p53 database [Olivier
uterus, lymphoma, and leukemia. These occur primar- et al., 2002] revealed that the majority of missense
ily as a consequence of an endogenous mutation mutations cluster in the central DNA binding domain,
mechanism. Endogenous mutations result from errors whereas insertions, deletions, and stop codons repre-
occurring during DNA metabolism and repair, e.g., sent major events in the N-terminus and the C-
mismatch repair deficiency in colon cancer (mutator terminus of p53. Frameshift mutations can lead to
phenotype). Oxyradicals such as NO generated by phenotypes different from that observed with missense
nitric oxide synthase 2 also contribute to p53 mutations mutations [Soussi and Beroud, 2001].
in colon cancer [Ambs et al., 1998]. In addition to mutational inactivation, p53 func-
Cancer types with low CpG transitions demon- tions are abrogated by allelic loss in many cancers.
strate high G:C to T:A transversions and are associated Approximately 50% of all cancer cases involve missense
with exogenous risk factors. A strong correlation exists mutations of one p53 allele coupled with a deletion of
between transversions and tobacco use in lung and the second allele [Hollstein et al., 1991]. Loss of
bladder cancer, UV exposure in melanoma, and heterozygosity (LOH), which has been seen among
exposure to aflatoxin B1 in liver cancer. In lung cancer, many members of Li-Fraumeni families, has been
50% of the mutations are G to T transversions, and linked to early onset of cancers [Kleihues et al., 1997;
they frequently occur at codons 157,158, 248, 249, and Malkin et al., 1990]. A high percentage of p53 LOH has
273. Mutations at codons 157 and 158 are rare in other been reported in gastric carcinoma [Fenoglio-Preiser
cancers. G to T transversion in codon 249 is a very et al., 2003], in colorectal cancer [Khine et al., 1994]. It
common mutation among patients with hepatocellular has been suggested that mutational events precede p53
carcinoma (HCC) and represents 90% of all HCC allelic loss in the progression from early to late stage
mutations. Worldwide epidemiological studies show disease at least in gastric carcinoma [Fenoglio-Preiser
that mutation in codon 249 is strictly specific to et al., 2003].
countries in which food is contaminated with aflatoxin
[Ozturk, 1991]. Acrylamide present in various dyes has Prognostic Value of p53 Mutations in Cancer
been linked to bladder cancer and primarily induces G Given the importance of p53 in tumor suppres-
to C transversion. G:C to C:G mutations at codons 280 sion, inactivation of the p53 pathway would be
and 285 are hotspot p53 mutations. expected to lead to the selection of more aggressive
The mutation spectrum in nonmelanoma skin tumors with a high degree of genetic instability. p53
cancers shows a very high frequency of C to T inactivation would be expected to be associated with
transitions mainly at dipyrimidine sites. The localiza- poor prognosis including disease recurrence and
tion of CC to TT mutations in skin cancer shows reduced overall survival.
striking differences with other type of cancers, with A prospective study of 271 women with primary
hotspot codons at 177–179 and at codon 248, probably breast cancer indicated that patients with p53 muta-
because of exceptionally slow repair of UV-induced tions had significantly greater breast-cancer-specific
lesions at these codons [Brash et al., 1991; Tornaletti mortality than did patients without p53 mutations [Lai
and Pfeifer, 1994]. et al., 2004]. Further analysis of mutation character-
These differences in mutational events targeting istics patients suggested that not just p53 mutation per
various codons in different cancers are caused by se but the precise nature of the mutation needs to be
P53 TUMOR SUPPRESSOR AND CANCER CHEMORESISTANCE 257

examined when it is used as a prognostic marker [Lai In addition to p53 mutations in tumors, a
et al., 2004]. Many other studies reported that p53 common polymorphism of p53 at codon 72 resulting
mutation is an independent predictor of poor prognosis in either a protein with a proline residue or an arginine
in colorectal cancer [Ahnen et al., 1998; Haseba et al., residue has been reported to associate with human
2003], serous ovarian cancer [Lassus et al., 2003], early cancer susceptibility [Buchman et al., 1988]. This
breast cancer [Linjawi et al., 2004], bladder cancer [El- polymorphism is distributed along a north/south axis
Kenawy et al., 2003], and adenocarcinomas in Barrett’s in the Northern Hemisphere. The arginine allele is
esophagus [Schneider et al., 2000b]. p53 mutation or more frequent in the north of Europe and in the
overexpression also has an unfavourable impact on United States, whereas the prevalence of the proline
prognosis [Mitsudomi et al., 2000] and survival in allele increases near the Equator [Weston and God-
patients with non–small-cell lung cancer [Steels et al., bold, 1997]. It has been suggested that the proline
2001]. allele, which is present in high frequency in the African
Information on the nature and site of the p53 population, may have a protective role in skin cancer
mutation as well as the genetic background of patients [Beckman et al., 1994]. In fact, a relationship between
is critical for correlative studies. A number of publica- the presence of the arginine allele and susceptibility to
tions reporting p53 mutations in human cancers sunburn and skin cancer has been reported [McGregor
resulted from small-scale studies with little information et al., 2002]. Recent studies have found that the
on exact pathologies and therapeutic protocols, com- arginine allele is preferentially retained in neoplastic
plicating the interpretation of the results. Some studies tissue of patients affected by common carcinomas
used only part of the p53 coding sequence, exons 5–8, including vulval, urinary tract, lung, and breast cancer
for mutation analysis. Recent studies focusing on either [Bonafe et al., 2003; Brooks et al., 2000; Furihata et al.,
the entire gene or on exons 4–10 have found a good 2002; Papadakis et al., 2002]. Conformational p53
correlation between p53 mutations and poor outcome mutants with the arginine allele have an enhanced
in non–small-cell lung carcinoma [Hashimoto et al., pathological role, particularly in tissues that normally
1999; Skaug et al., 2000; Tomizawa et al., 1999], express high levels of the p53 homologs, p63 and p73
whereas no prognostic significance was found when the [Marin et al., 2000], and has been shown to be
analysis was restricted to exons 5–8 [Schiller et al., associated with reduced sensitivity to cancer therapy in
2001]. Differences in structure and function of various head and neck cancer [Bergamaschi et al., 2003]. In
p53 mutants may contribute to heterogeneity in clinical addition to the nature of mutation and polymorphism
response. Because human carcinomas clearly select for of p53, the genetic background of a patient in relation
p53 missense mutations (rather than deletion/inser- to the expression status of p63 and p73 may be
tions and frameshifts), additional oncogenic mechan- important for evaluating prognosis.
isms may occur. In addition to interfering with wild-
type p53 functions, some mutant p53 proteins might Other Factors Influence the Prognostic Value of p53
increase oncogenic potential [Dittmer et al., 1993; Mutation
Harvey et al., 1995]. p53 with mutation R175H has There are contradictory reports in the literature,
been shown to be associated with increased resistance indicating that p53 mutation is not an independent
to etoposide, a DNA-damaging chemotherapeutic prognostic factor in cancer. Mutations or altered
agent [Blandino et al., 1999]. In breast [Kucera et al., expression of p53 downstream target genes or up-
1999] and colon cancer [Borresen-Dale et al., 1998], stream regulators (e.g., ATM, Chk2, Hdm2, and
there is a strong association between mutations in the p14ARF) also occur in human tumors (see below). As
L2/L3 loop of the p53 DNA binding domain and a result, the presence of wild-type p53 does not
shorter survival and poor response to treatment. In indicate that the p53 pathway is intact. This compli-
head-and-neck cancer, patients with p53 mutations at cates the effort to correlate p53 gene status with drug
residues in direct contact with target DNA fared response.
less well than those with mutations elsewhere in the In addition, there are recent reports that prog-
p53 structure [Erber et al., 1998]. p53 sequence nosis in cancer patients depends on multiple factors in
analysis remains an expensive and labor-intensive addition to p53 mutations. For example, the evaluation
process. With the improved technologies for accurate of p53 mutations and p53 protein accumulation in a
determination of p53 mutations [Tonisson et al., 2002], cohort of 178 patients with early-stage ovarian carci-
described below, a better understanding of the nomas found that p53 accumulates in 32.6% of all
behavior of each mutation will allow us to develop tumors and concluded that neither p53 mutations nor
better correlations between p53 mutation and clinical p53 protein accumulation influenced the prognosis
prognosis. significantly in this group of patients [Wang et al.,
258 LIU ET AL.

2004b]. Interestingly, a cohort study of a series of 543 Tumor cells with inactivated p53 generally display
women with node-negative breast cancer suggested a stronger resistance to cytotoxic drugs, which can be
that the combination of p53 mutation and ErbB2 explained by a nonfunctional G1/S checkpoint and a
amplification might help to identify women at higher reduced sensitivity to apoptosis [Petty et al., 1994]. The
risk of disease recurrence and death. In contrast, the relationship between p53 status and chemosensitivity
presence of p53 mutation may not provide additional or radiosensitivity has been extensively studied [El-
independent prognostic information in the absence of Deiry, 2003; Ferreira et al., 1999; Pirollo et al., 2001].
ErbB2 amplification [Bull et al., 2004]. Similar results For example, 35 patients with locally advanced breast
were observed in breast tissues obtained from 506 cancer were investigated for p53 mutations before
patients with invasive ductal carcinoma [Yamashita receiving combination chemotherapy with 5-fluorour-
et al., 2004]. acil and mitomycin administered in the neoadjuvant
Mutations in K-ras codon 12 and p53 are setting [Geisler et al., 2003]. The results revealed a
common abnormalities in colorectal cancer. A recent significant association between lack of response to 5-
study indicated that simultaneous mutations in K-ras fluorouracil and mitomycin and mutations affecting the
and p53 are indicative of a worse prognosis in sporadic L2/L3 domains of the p53 protein. In addition, studies
colorectal cancer. This may be explained by the fact with the cell lines used for NCI cancer drug screening
that transformation by Ras requires either a cooperat- demonstrated that cells with mutant p53 showed
ing oncogene or the inactivation of tumor suppressors decreased response to chemotherapeutic drugs com-
such as p53 [Gonzalez-Aguilera et al., 2004]. The pared to cells harboring wild-type p53 [O’Connor et al.,
combined effects of p53, p21, and pRb expression were 1997]. The relationship of p53 gene mutation and
observed to behave in cooperative or synergistic ways response to topoisomerase II inhibitors was also
to promote bladder cancer progression, suggesting assessed in non–small-cell lung cancers in an ex vivo
additional limitations to the use of a single determinant study [Vogt et al., 2002]. The results indicated that
[Chatterjee et al., 2004; Shariat et al., 2004]. Bcl-2 and tumor cells with p53 mutations were significantly
p53 are closely linked in the regulation of apoptosis. A resistant to etoposide and epirubicin. A number of
cohort study of 308 patients with gastric cancer [Lee other studies also demonstrated that p53 gene status
et al., 2003] showed that a high level of p53 protein correlates well with the tumor response to cytotoxic
expression showed a significantly poorer prognosis. A drugs in ovarian cancer [Pestell et al., 1998; Reles et al.,
combined assessment of p53 and Bcl-2 expression 2001; Righetti et al., 1996; Sato et al., 1999], malignant
showed that patients with p53(+)/Bcl-2() tumors glioma [Iwadate et al., 1996], head and neck squamous
showed significantly worse 5-year survival (57%) than cell carcinoma [Bradford et al., 2003], breast cancer
the other groups. The best survival was seen in the [Clahsen et al., 1998] and non–small cell lung cancer
group with p53(+)/Bcl-2(+) tumors (100%), suggesting [Levesque, 1998]. Introduction of wild-type p53 into
Bcl-2 expression may have potential prognostic value tumor cells using adenoviral vectors increased response
when combined with p53 expression [Lee et al., 2003]. to cisplatin, doxorubicin, 5-fluorouracil, methotrexate,
In a study of 156 patients with curatively resected or etoposide in a variety of cancer cell lines including
gastric cancer, positive correlations between tumor head and neck, ovarian, prostate, and breast cancer
microvessel density and both p53 (P ¼ 0.005) and [Gurnani et al., 1999; Nielsen et al., 1998].
VEGF (P ¼ 0.005) expression were observed. Patients The majority of these studies suggest that the
whose tumors did not show p53 protein overexpression presence of wild-type p53 may benefit cancer patients’
(usually indicating mutant p53) had a survival benefit response to chemotherapy. However, the impact of p53
compared to those expressing p53 when treated with status on drug sensitivity of tumor cells remains
adjuvant chemotherapy (P ¼ 0.01) [Fondevila et al., controversial. For example, it was reported that
2004]. small-cell lung cancer and advanced rectal cancer were
not sensitized to cytotoxic drugs in the presence of
wild-type p53, whereas c-myc protein was found to be
P53 MUTATIONS AND CHEMOSENSITIVITY involved in induction of apoptosis in response to
Tumor prognosis is determined by a combination genotoxic stress [Elsaleh et al., 2000; Supino et al.,
of the intrinsic aggressiveness of the tumor and 2001]. Wild-type p53 has been shown to potentiate the
potential sensitivity to chemotherapy. A study of late- cytotoxic effect of 5-fluorouracil in colon cancer cell
stage colorectal cancers indicated that the poor lines [Yang et al., 1996], and p53 mutations did not
prognosis of stage IV colorectal cancers with p53 affect response to cytotoxic drugs in breast cancer
overexpression was associated with their poorer che- [Elledge et al., 1995; Linn et al., 1997]. These
mosensitivity [Liang et al., 2002]. contradictory reports are likely explained by multiple
P53 TUMOR SUPPRESSOR AND CANCER CHEMORESISTANCE 259

factors, including the mutation detection method used, treatment [Irwin et al., 2003]. Mutant p53 may bind to
cancer stage and heterogeneity, gain-of-function muta- p73 protein and inactivate its function, rendering the
tions of p53, and functional mutations or altered cancer cells resistant to DNA-damaging drugs.
expression of other genes in the p53 pathway.
Kemp et al. reported that the p53 gene status and BIOLOGICAL BASIS OF P53-ASSOCIATED DRUG
response to chemotherapy are different, depending on RESISTANCE AND STRATEGIES FOR IMPROVING
the tumor tissue origin [Kemp et al., 2001]. Their CANCER THERAPY
results suggested that the apoptotic response to The relationship between mutant p53 expression
chemotherapy is dependent on the tumor origin rather and chemoresistance of tumors is not fully defined.
than p53 gene status. The authors suggested that tumor Defining additional molecular markers of drug sensi-
derived from tissues that are prone to p53-dependent tivity that may modulate the role of p53 mutation holds
apoptosis are susceptible to cytotoxic and radiation promise for more precise matching of appropriate
therapy. Cancers of hematopoietic/immune, reproduc- chemotherapy to individual patients.
tive/endocrine cells are more sensitive to chemother-
apy and radiation therapy than cancer originating from Regulators of p53
lung, kidney, and liver [Gudkov and Komarova, 2003]. Wild-type p53 is a short-lived protein and is
In addition to tissue type variation to chemosensitivity, tightly maintained at a low level in normal cells by
cancer response to chemotherapy is also affected by ubiquitination and proteasomal degradation. p53 is
other preexisting molecular and genetic alterations, significantly activated in response to DNA damage, UV
including Bcl-2 [Harada et al., 2003; Violette et al., light, activation of oncogenes, and hypoxia [Vogelstein
2002], p16INK [Raghavan, 2003], PTEN [Mayo et al., and Levine, 2000; Wahl and Carr, 2001]. Central to this
2002], and BRCA1 [Fedier et al., 2003c; Goffin et al., regulation of p53 is the Hdm2 protein (Fig. 2). Hdm2
2003]. Recently, a member of the p53 family, p73, has is a negative regulator of p53 function through direct
been linked to chemosensitivity to cis-platinum, binding and subsequent relocalization and degradation
doxorubicin HCl (Adriamycin, Pharmacia and Upjohn, of p53 protein [Juven et al., 1993]. Transcription of the
MI), and paclitaxel (Taxol, Bristol-Myers Squibb, NY) Hdm2 gene is strongly activated by p53 [Vargas et al.,

Fig. 2. Schematic representation of the genes upstream and downstream of the tumor suppressor p53 discussed in the text. p53 is subject to
feedback regulation through p14ARF repression and p53-dependent Hdm2 transactivation.
260 LIU ET AL.

2003]. As illustrated in Figure 2, the negative class of inhibitor clearly has potential in treating tumors
autoregulatory feedback loop allows the tight regula- harboring wild-type p53. It also can to be used in
tion of p53 activity and stability [Momand et al., 2000]. combination with cytotoxic drugs probably more likely
In general, mutations in p53 gene and amplification of with DNA damage (e.g., Adriamycin) to boost the
Hdm2 do not occur within the same tumor. Most function of p53 and the cellular response to
Hdm2 amplification-positive tumors have wild-type chemotherapy.
p53, indicating that overexpression of Hdm2 is an Hdm2 functions as a ubiquitin E3 ligase that
independent means of inactivation of p53 [Momand promotes the ubiquitination of p53, targeting it for
et al., 1998]. Double-positive phenotype for p53 and degradation by the proteasome [Haupt et al., 1997;
Hdm2 (mutations in p53 gene and amplification of Honda et al., 1997]. Inhibition of the E3 ligase activity
Hdm2) was suggested as the most potent predictive of Hdm2 may stabilize wild-type p53 protein and
factor of doxorubicin resistance in breast cancer restore p53 tumor suppressor function in tumors. E3
patients [Suzuki et al., 1998]. Hdm2 was found to be ligase inhibitors could potentially be used to sensitize
localized to the nucleus, and expression of the PTEN tumor cells in combination with chemotherapy or
tumor suppressor was lost in the doxorubicin-resistant radiation therapy. Small-molecule inhibitors have been
acute lymphoblastic leukemia (ALL) lines [Zhou et al., reported that specifically inhibit Hdm2-mediated p53
2003]. In contrast, Mdm2 was aberrantly localized to ubiquitination in vitro [Lai et al., 2002]. Their cellular
the cytoplasm in ALL lines that express high levels of inhibitory activity and therapeutic potential remain to
PTEN and are sensitive to doxorubicin. Importantly, be further explored. The approach of inhibiting Hdm2
this study suggests that PTEN reverses Hdm2- E3 ligase activity is justified by several observations.
mediated chemotherapy resistance through physically First, p14ARF, an endogenous inhibitor of Hdm2
binding to p53 and diminishing Hdm2-mediated p53 activity, acts upstream of p53 by binding to Hdm2,
inhibition [Zhou et al., 2003]. interfering with the E3 ligase activity of Hdm2, thus
Antisense to Hdm2 specifically inhibits Hdm2 promoting the stabilization of p53 (Fig. 2) [Honda and
expression and has demonstrated significant anti-tumor Yasuda, 1999]. The INK4a/ARF locus is frequently
activity in vitro and in vivo [Zhang and Wang, 2003b]. mutated in human cancers [Sherr, 2001]. These
Furthermore, antisense to Hdm2 increased sensitivity mutations have been linked to chemoresistance
to the chemotherapeutic agents irinotecan, paclitaxel, through disabling p53 [Schmitt et al., 1999]. As
and rituximab (Rituxan, Genentech, CA) as well as expected, transfer of p14ARF gene into drug-resistant
radiation therapy in nude mice bearing a variety of human breast cancer cells inhibits proliferation and
human cancer xenografts [Wang et al., 2003b; Zhang et reduces doxorubicin resistance [Guo-Chang and Chu-
al., 2004]. This provides a rationale for identification of Tse, 2000]. Second, Velcade (PS-341), a selective and
a Hdm2 inhibitor for chemosensitization and radio- potent inhibitor of the proteasome, is approved for
sensitization. treatment of patients with relapsed refractory multiple
Co-crystal structure of hdm2 bound to a p53 myeloma [Voorhees et al., 2003]. This provides clinical
peptide showed that the p53 binding region of Hdm2 validation of the ubiquitin/proteasome pathway as a
forms a deep hydrophobic pocket, suggesting it might therapeutic target in oncology. It is interesting to
be accessible by small molecules. A large effort has observe that molecular changes after PS-341 treatment
been under way in the past several years to identify are associated with the negative regulator of p53,
small molecule inhibitors of the Hdm2–p53 interaction Hdm2. For example, the antitumor activity of PS-341 is
[Chene, 2003]. Although some of these inhibitors associated with induction of p53 and Hdm2 and
possess reasonable potency in the in vitro binding activates p53 through the phosphorylation of p53 on
assay, their biological (cell-based) potency is still serine 15 in the early time point, and activation of c-Jun
limited. A breakthrough was achieved recently by NH2-terminal kinase (JNK) and caspases, which, in
scientists at Roche who identified a small-molecule turn, cleaves degradation of Hdm2 when apoptosis
imidazoline analog from high throughput screening takes place in the late time point [Hideshima et al.,
[Vassilev et al., 2004]. Additional optimization of the 2003]. Given the clinical promise of PS-341 in patients
lead molecule through medicinal chemistry yielded a with multiple myeloma, these studies provided a
potent inhibitor (Nutlin-3a) with IC50 of E90 nM. further rationale for the development of the targeted
Nutlin-3a exhibited potent cellular activity, increasing therapy on Hdm2.
p53 and p21 protein expression and inhibiting cell The Hdm2-p53 negative feedback system is
proliferation. Importantly, oral administration of Nu- regulated at multiple levels through many different
tlin-3a resulted in tumor growth inhibition in a mouse mechanisms (Fig. 2). For example, ATM, the gene
xenograft model with no overt signs of toxicity. This product mutated in ataxia–telangiectasia, is a PI-3-like
P53 TUMOR SUPPRESSOR AND CANCER CHEMORESISTANCE 261

kinase [Savitsky et al., 1995; Vogelstein and Levine, original theme of dependency of Chk1 on ATR, and
2000]. Its homologue, ATR (ataxia telangiectasia Chk2 on ATM, has recently been modified by reports
related), carries out checkpoint-related functions that of various ‘‘crosstalk’’ among these kinases (Fig. 1)
partially overlap with those performed by ATM. Both [Bartek and Lukas, 2003; Liu et al., 2000; Matsuoka
ATM and ATR contribute to the phosphorylation and et al., 1998]. Concomitant inactivation of p53 and Chk2
activation of p53 after exposure to g- or UV radiation was observed in breast cancer [Sullivan et al., 2002].
(Fig. 2) [Banin et al., 1998; Tibbetts et al., 1999]. The Using dominant negative Chk1 mutant, both check-
third PI-3-like kinase, DNA-dependent protein kinase point abrogation and clonogenic radiosensitization of
(DNA-PK), also plays a crucial role in the repair of HeLa cells has been demonstrated without dramatic
damaged DNA and the phosphorylation of serine 15 on effects on cell proliferation in the absence of extrinsic
p53 (Fig. 2) [Burma et al., 1999]. The exposure to the DNA damage [Koniaras et al., 2001]. Most importantly,
radiosensitizing agent caffeine sensitizes tumor cells to inhibition of the Chk1-dependent G2 DNA damage
ionizing radiation through the inhibition of ATM, ATR, checkpoint in p53-deficient cells greatly sensitizes the
and DNA-PK kinase activities. This in turn inhibits g- cells to radiation [Koniaras et al., 2001], suggesting the
and UV radiation-induced phosphorylation of serine 15 necessity of the G2 checkpoint for the response of p53-
on p53 and abrogates the G2 checkpoint in response to dependent checkpoint-deficient tumors. Furthermore,
ionizing radiation [Block et al., 2004; Sarkaria et al., it was reported that UCN-01, a known inhibitor of cell
1999]. cycle arrest at the G2 checkpoint, preferentially
ATM, ATR, and DNA-PK interact with p53 and radiosensitized p53 mutated cancer cells, and showed
may also have p53-independent functions. Loss of synergistic growth inhibition in combination with
ATM function in p53-deficient cells has been reported camptothecin or mitomycin C in p53 mutated cancer
to increase the sensitivity to topoisomerase I poisons cells versus wild-type p53 tumor cells [Jones et al.,
(e.g., camptothecin), topoisomerase II poisons (e.g., 2000; Sugiyama et al., 2000; Xiao et al., 2002; Yao et al.,
doxorubicin), and to antimetabolites (e.g., gemcita- 1996]. It has been shown that UCN-01 prevented
bine), but not to platinum agents or taxanes [Fedier et ionizing radiation–induced p53 upregulation and p53
al., 2003b]. The increased chemosensitivity of ATM- phosphorylation on serine 20, a site identified for Chk2
deficient cells was not accompanied by increased (or/and Chk1) kinase [Yu et al., 2002]. The G2
apoptosis or further alteration of cell cycle checkpoint checkpoint may be critically important because many
activation, suggesting that ATM may play a role in tumors have acquired defects in the G1 checkpoint
protective response to DNA damage independent of because of alterations of the p53 and pRb pathways,
p53. In addition, the disruption of the DNA-PK gene in making them highly dependent on the G2 checkpoint
p53-deficient cells has been demonstrated to cause an to survive DNA damage. This explains why G2
increase in sensitivity to doxorubicin and epirubicin checkpoint abrogators, such as UCN-01, can sensitize
[Fedier et al., 2003a]. Doxorubicin-induced hypersen- the antiproliferative activity of ionizing radiation or
sitivity in these cells correlated with transient G2/M chemotherapeutic agents in p53-deficient cells. Inhi-
checkpoint activation, suggesting that DNA-PK mod- bitors targeting Chk1 and Chk2 could potentially
ulates p53-independent pathways in response to DNA improve the therapeutic window of available DNA
damage induced by anthracyclines [Fedier et al., damaging agents, especially in the treatment of cancers
2003a]. Therefore, the inhibition of function of ATM, that carry a mutant p53 gene.
ATR, or DNA-PK in tumors may be a valuable
approach to improve chemosensitivity in the treatment p53 Downstream Target Genes
of cancers that carry mutant p53. p53 is a transcription factor that regulates sets of
Arrest in the G2 phase of the cell cycle in genes by transcriptional activation and repression.
mammals has been shown to require CHK proteins Recently, bioinformatics and microarray approaches
[Hirao et al., 2000; Liu et al., 2000]. Chk2 functions have been used to assess the transcriptional targets of
downstream of ATM to directly phosphorylate p53 at p53 in the human genome and the global transcrip-
serine 20. Phosphorylation of serine 20 is known to tional program during the process of p53-induced
interfere with Hdm2 binding [Hirao et al., 2000]. apoptosis and cell cycle arrest [Mirza et al., 2003; Wang
Radiation-induced phosphorylation of Chk1 at S345 et al., 2001].
induces physical association with p53 and is involved in The primary basis for drug resistance in tumors is
p53-dependent cell cycle arrest [Tian et al., 2002]. most likely dysregulation of apoptosis. The direct
Chk1 can be phosphorylated/activated by ATR and/or relationship between p53, apoptosis, and drug response
ATM in response to UV radiation and ionizing implies that activating apoptotic pathways that are
radiation, respectively [Bartek and Lukas, 2003]. The directly downstream of p53 may have clinical benefits.
262 LIU ET AL.

Survivin, a member of the inhibitor of apoptosis through sequence-specific binding sites in their pro-
protein family, inhibits apoptosis by blocking caspase- moters (Fig. 2) [Goldsmith et al., 1995; Strauss and
3 and -7 activation [Shin et al., 2001]. It has been Haas, 1995b]. A subset of mutant p53 proteins strongly
reported that survivin is repressed by p53 (Fig. 1) and activate the transcription of MDR1 and MRP1 genes
overexpressed in many tumors, implicating a role in [Nguyen et al., 1994; Strauss and Haas, 1995a; Sullivan
maintenance of tumor cell viability and in resistance to et al., 2000; Tsang et al., 2003].
a variety of apoptotic stimuli, including chemotherapy A strong correlation exists between the expression
[Adida et al., 1998; Altieri et al., 1999; Ambrosini et al., of mutant p53 and MDR1 in breast tumors [Linn et al.,
1997; Grossman et al., 1999; Hoffman et al., 2002; 1996; Linn et al., 1997; Moriki et al., 1995]. Further-
Mirza et al., 2002; Saitoh et al., 1999; Tanaka et al., more, 143 breast tumor patients, who underwent either
2000]. Expression of survivin correlates with Taxol one of two different chemotherapeutic regimens
resistance in human ovarian cancer [Zaffaroni et al., (epirubicin versus cyclophosphamide), were analyzed
2002], and survivin serves as a predictor of platinum for expression of a number of different proteins both
sensitivity in gastric cancer patients [Nakamura et al., before and after therapy. The results indicated that
2004]. Transgenic expression of survivin inhibited mutant p53 strongly correlated with MDR1 expression
UVB-induced apoptosis in vitro and in vivo, and in tumor samples and was an independent predictive
correlates with loss of p53 [Grossman et al., 2001]. factor for poor response [Bottini et al., 2000]. Similar
Antisense-mediated downregulation of survivin expres- co-expression of mutant p53 and MDR1 was observed
sion sensitizes human lung, breast tumor cells, and in osteosarcoma [Park et al., 2001]. Nevertheless, in
melanoma cells to chemotherapy [Choi et al., 2003; prostate tumors where p53 expression is strongly
Olie et al., 2000; Pennati et al., 2004]. These findings correlated with surgical stage and chemoresistance,
suggest that survivin is an attractive drug target MDR1 is not expressed at any stages while MRP1 is
candidate for new cancer therapeutics. In addition, overexpressed in advanced stage disease [Sullivan et al.,
many other proapoptotic genes have been implicated in 1998; Van Brussel et al., 2001]. Upregulation of MRP1
the cellular response to chemotherapy [Sax and El- and increase in drug resistance were found to be
Deiry, 2003; Sax et al., 2002], whereas other p53- induced by p53 mutation [Sullivan et al., 1998; Tsang et
induced genes (e.g., p53R2, XPC, and XPE) have been al., 2003]. Several compounds that inhibit MRP1 or
shown to be directly involved in DNA damage response MDR1 have been proposed to be useful in the
and repair [Adimoolam et al., 2002; Takimoto et al., treatment of drug-resistant tumors [Peck et al., 2001;
2002; Tanaka et al., 2000; Tang and Chu, 2002]. Wang et al., 2003a; Wang et al., 2004a]. However, some
The p21 gene plays an important role in p53- published studies report a lack of correlation between
mediated growth suppression, DNA repair, and apop- p53 mutation and MDR expression. Analyses of 64
tosis. As expected, p53 and p21 status affects chemo- breast tumor samples suggested no significant correla-
sensitivity. It has been shown that p53 negative/p21 tion between p53 mutations and MDR1 expression
positive immunostaining (n ¼ 12) may be a predictor of [Chevillard et al., 1997]. Similar observations were
favorable response to two DNA-damaging drugs, made with expression analysis of MDR1 and p53 in 48
cisplatin and pirarubicin, in patients with locally locally advanced breast biopsies [Schneider et al.,
advanced bladder cancer. The objective response rate 2000a].
in these patients was 92%, significantly higher than that Interestingly, it was reported that cells carrying
of the p53 positive and/or p21 negative group (45%, p53 mutations were more sensitive to taxanes but
n ¼ 11) (P ¼ 0.027) [Koga et al., 2000]. However, many resistant to vinca alkaloids [Wahl et al., 1996; Zhang et
studies have shown that p21 can have pro- or al., 1998]. p53-dependent repression of MAP4 may
antiapoptotic functions in response to antitumor explain this altered sensitivity of tumor cells to
agents, depending on the cell type and cellular context. microtubule agents [Zhang et al., 1999; Zhang et al.,
This dual role of p21 in cancer cells complicates 1998]. MAP4 is transcriptionally repressed by p53 (Fig.
using p21 status to predict drug response [Liu 2) [Murphy et al., 1996]. Overexpression of MAP4
et al., 2003]. (when p53 is transcriptionally inactive) increases
The most common alterations in drug transport, polymerization of microtubules, cellular binding of
which can lead to drug resistance, are increased paclitaxel, and sensitivity to paclitaxel, a drug that
expression of multidrug resistance gene-1 (MDR1) inhibits microtubule depolymerization [Zhang et al.,
and the multidrug resistance-associated protein 1998]. In contrast, overexpression of MAP4 led to a
(MRP1) [Borst et al., 2000; Johnstone et al., 2000]. It shift of tubulin dynamics from monomers to polymers
has been reported that wild-type p53 negatively and decreased sensitivity to vinca alkaloids, drugs that
regulates the expression of MDR1 and MRP1 genes bind to tubulin monomers and inhibit microtubule
P53 TUMOR SUPPRESSOR AND CANCER CHEMORESISTANCE 263

polymerization [Zhang et al., 1998]. Repression of tions, indicates that mutant protein has less thermo-
MAP4 by UV irradiation, bleomycin, or doxorubicin dynamic stability at physiological temperature [Cho
(through induction of wild-type p53) was associated et al., 1994]. The restoration of wild-type p53 function
with decreased sensitivity to paclitaxel and increased to mutant protein by second-site suppressor mutations
binding of and sensitivity to vinca alkaloids [Zhang et that increase thermodynamic stability of the core
al., 1999]. DNA damage did not alter the sensitivity of domain confirms this hypothesis [Baroni et al., 2004;
nonmicrotubule-active drugs [Zhang et al., 1999]. Nikolova et al., 2000]. Novel drugs capable of
Therefore, the alterations in drug sensitivity were reactivating mutant p53 would have tremendous
consistent with the function of MAP4 to promote the impact in cancer treatment. The relatively longer
polymerization and stabilization of microtubules. The half-life of mutant p53, with detectable protein
results from a phase I/pilot study demonstrated the expression being specific to cancer cells, may provide
ability to detect the activation of p53 and the repre- the necessary tumor selectivity for these classes of
ssion of MAP4 in normal and malignant mammary molecules. Over the past few years, a number of small
tissue in patients treated with DNA-damaging agent molecules and peptides that reactivate some mutant
(doxorubicin) and the relative safety of delivering forms of p53 have been identified and characterized
doxorubicin followed in sequence by an antimicrotu- [Bykov et al., 2002; Foster et al., 1999; Issaeva et al.,
bule drug (vinorelbine) at a time when cells may be 2003]. Both of the small molecules CP31398 and
more sensitive to treatment [Bash-Babula et al., PRIMA1 have been shown to restore DNA binding
2002]. This study suggests that future studies in breast activity, induce apoptosis in cancer cells expressing
cancer patients that carry wild-type p53 are warranted various mutant p53, and inhibit tumor growth in animal
of drug response to determine whether activation of models. It is possible that these molecules may act as
p53 and repression of MAP4 are good predictive chaperones to stabilize the conformation of the DNA
factors. binding domain of mutant p53 [Friedler et al., 2002];
however, the biochemical and biophysical characteriza-
Overcoming Chemoresistance in p53-Deficient tion of these interactions is incomplete. Some of these
Tumors molecules and their possible mechanism of actions
Although p53 mutations are common in many were recently reviewed [Bykov et al., 2003]. Under-
human cancers, only 2% of neuroblastomas are standing the mechanism of action of these molecules
reported to have p53 mutations [Vogan et al., 1993]. will improve our prospects for discovering potential
Most high-risk neuroblastoma patients develop recur- therapeutics.
rent disease that is refractory to chemotherapy. Upon DNA mismatch repair (MMR) proteins play an
recurrence, these neuroblastomas acquire a high-level important role in the maintenance of genomic stability.
of drug resistance, and abrogation of p53 function Interestingly, loss of MMR gene, MLH1, can result in
[Keshelava et al., 2000]. Nonmutational inactivation of an increased sensitivity to cisplatin in p53-deficient
p53 function in neuroblastomas has been suggested to human colon cancer cells [Lin et al., 2001]. Further-
be attributable to cytoplasmic sequestration and more, with the concomitant loss of function of Pms2,
defective translocation of p53 [Ostermeyer et al., another MMR gene, p53-deficient cells were rendered
1996]. Therefore, identifying drugs that are p53 hypersensitive to platinum compounds, topoisomerase
independent may provide agents active against recur- II poisons, taxanes, and the antimetabolite gemcitabine
rent, drug-refractory neuroblastomas. A recent study [Fedier et al., 2002]. Together, these data suggest that
showed that prolonged systemic exposure to pyrazo- MLH1 or PMS2 could be a putative protective
loacridine (PZA), a novel DNA intercalator, is effective mediator of cell survival in p53-deficient cells. Similar
in drug-resistant p53-nonfunctional neuroblastomas effects were observed for the loss of BRCA1 on the
cell lines [Keshelava et al., 2003], suggesting the chemosensitivity in p53-deficient cells [Fedier et al.,
potential of PZA in future cancer therapy. 2003c].
Because a large portion of human cancers are BRCA1 is also involved in the cellular response
functionally p53 deficient, and hence may be resistant to DNA damage. Additional loss of BRCA1 in
to chemotherapeutic agents, identifying a means of p53-deficient cells reverses chemoresistance to
sensitizing p53-deficient tumors is of great importance. the topoisomerase I poisons, topoisomerase II
Reactivation of mutant p53 in tumors has become an poisons, and to platinum agents, but not to taxanes or
attractive strategy for developing novel therapeutics as the antimetabolites 5-fluorouracil and gemcitabine
more is understood about the mutational defects in p53 [Fedier et al., 2003c]. This suggests that BRCA1
protein. The crystal structure of the p53 core domain, may play a role in protecting cells from apoptosis-
which harbors most of the oncogenic missense muta- mediated cell death in p53-deficient cells, and BRCA1
264 LIU ET AL.

modulates p53-independent DNA damage response These studies demonstrate the potential of tissue
pathways. microarray in rapid analysis of clinical molecular
alterations.
ADVANCES OF PHARMACOGENOMIC RESEARCH
OF P53 Single Nucleotide Polymorphism Genotyping of the
As described above, a large number of studies p53 Gene
have been carried out to examine the role of p53 gene Direct sequencing is commonly used for detect-
mutations or protein expression as a prognostic or ing p53 mutations. However, this method is labor
predictive factor in human cancer. To date, their use intensive and costly. A recent technology to detect p53
has not been implemented routinely in clinical sequence alterations is the p53 GeneChip derived from
practice. In recent years, technological achievements light-generated oligonucleotide arrays [Pease et al.,
have fostered a renewed interest in the pharmacoge- 1994]. The array contains oligonucleotide probes
nomics of p53 and its role in drug response. synthesized by light-directed combinatorial chemistry
with the wild-type p53 sequence in addition to the
High-Throughput Tissue Microarray Analysis of p53 sequences of the most commonly occurring p53
Protein Expression mutations. The relative binding of fragmented, labeled
High-throughput tissue microarray is a powerful template DNA to each probe in the array was
new tissue-conserving technology in the study of determined and evaluated for p53 mutations. The
cancer, allowing simultaneous study of a large number results of p53 sequence analysis of 100 primary human
of clinical tumor specimens on a single slide. The lung tumors using the p53 (GeneChip, Affymetrix, CA)
validation of tissue microarray technology from several were compared with the mutational analysis of the
laboratories suggests that tissue microarray is a reliable same tumors by direct sequencing [Ahrendt et al.,
technique to analyze the expression of markers, 1999]. The p53 GeneChip had 81% accuracy rate and
including p53, Ki-67, estrogen receptors, ErbB2, and 98% specificity compared with 76% accuracy rate and
vascular endothelial growth factor, in various carcino- 100% specificity for direct sequencing. In another
mas [Fernebro et al., 2002; Griffin et al., 2003; Jourdan study, the use of the p53 GeneChip in 108 ovarian
et al., 2003; Leversha et al., 2003; Rosen et al., 2004; tumor was also shown to be comparable to direct
Zhang et al., 2003a]. However, immunohistochemical sequencing [Wen et al., 2000]. In general, the use of
detection of p53 protein may either underestimate the p53 GeneChip provides relatively rapid analysis of the
frequency of p53 gene alterations (because not all p53 sequence as compared with direct sequencing
mutations lead to stabilization of p53 protein), or [Ahrendt et al., 1999]. Therefore, the p53 GeneChip is
overestimate p53 gene alterations (if p53 protein potentially rapid, adaptable to a clinical laboratory
accumulates because of reasons other than mutation setting, and permits the reasonable accurate analysis of
of the gene) [Scheffner, 1998; Sjogren et al., 1996]. a large volume of clinical samples.
Tissue microarray of 522 serous ovarian carcino- The ability to detect p53 gene alterations in DNA
mas was used to examine p53 expression immunohis- extracted from formalin-fixed, paraffin-embedded
tochemically [Lassus et al., 2003]. Both excessive (FFPE) breast cancer specimens was further evaluated
(mutant) and completely negative (null) p53 staining [Cooper et al., 2004]. The results indicated that the p53
(59% of the carcinoma) conferred poor patient out- GeneChip detected fewer gene alterations in DNA
come (P o 0.0001) and poor response to therapy (P o extracted from FFPE tissue than the direct sequen-
0.0001). In the most common subgroups, stage III and cing. However, if exon 4 is eliminated from the
stage I carcinomas, 5-year overall survival rates for evaluation, the p53 GeneChip detected significantly
patients showing normal p53 versus aberrant p53 were more mutations than direct sequencing. This suggests
72% versus 19% (P o 0.0001) and 99% versus 56% (P that it may be necessary to use a combination of the
o 0.0001), respectively. Therefore, p53 expression p53 GeneChip and direct sequencing for accurate
status classifies serous ovarian carcinoma into two identification of p53 gene alterations in FFPE tumor
distinct subtypes: one with a relatively good prognosis specimens.
associated with normal p53 expression, and the other
with a poor outcome associated with aberrant p53 Gene Expression Profiling to Identify Gene Signature
expression. Similar analyses were carried out with renal of p53-Associated Chemoresistance
cell carcinoma and endometrial carcinoma [Alkushi et The advent of cDNA/DNA microarray technol-
al., 2004; Zigeuner et al., 2004]. p53 immunoreactivity ogy and its capacity for simultaneous probing of the
was found to be a prognostic marker only for subtypes human genome on high-density cDNA microarray has
of renal cell carcinoma and endometrial carcinoma. allowed us to analyze the expression profiles of
P53 TUMOR SUPPRESSOR AND CANCER CHEMORESISTANCE 265

thousands of genes at once [Schena et al., 1996]. In that treatment responses are remarkably variable and
view of the complex array of genetic factors contribut- difficult to predict. Future challenges include classify-
ing to drug resistance, cDNA microarray is useful in ing genetic determinants of chemotherapeutics, and
comparison of gene expression profiles directly be- developing clinically feasible means of characterizing
tween the chemotherapy-sensitive group and the the genetic status of a given tumor. It is very likely that
resistant group in order to identify gene clusters and/ advanced solid tumors in humans harbor multiple
or markers whose expression changed significantly in genetically different subclones. There is no doubt that
the resistant group. For example, gene–drug relation- this inherent variability will remain a problem, even as
ships have been studied in NCI-60 human cancer cell we enter the era of targeted therapeutics. Complexities
lines using microarray technology to explore how the abound and many questions remain: Do genomic
variations in transcript levels of particular genes relate lesions need to be analyzed in detail? How much
to mechanisms of drug sensitivity and resistance genetic detail is needed? Or will expression profiles be
[Scherf et al., 2000]. adequate in practice? Nevertheless, the studies and
A microarray study examining the transcriptional new technologies described above provide a new
expression profiles of MCF-7 breast cancer cells paradigm to understand drug action and inherent
treated with 5-fluorouracil showed that SSAT, annexin variations in treatment resistance, and suggest that
II, thymosin-b-10, MAT-8, and chaperonin-10 were tumor genotype is a critical determinant of treatment
consistently upregulated, and each of these genes was outcome. These principles, when applied to human
found to have potential p53-responsive elements tumors, provide a strong rationale for individualized
[Maxwell et al., 2003]. p53 protein was observed to cancer therapy based on the understanding of drug
be induced in MCF-7 cells treated with 5-fluorouracil, action and knowledge of tumor types/subtypes.
and inactivation of p53 in an MCF-7-derived cell line Although numerous challenges remain towards imple-
(M7TS90-E6) resulted in significantly decreased 5- mentation of individualized therapy, with time, this
fluorouracil-mediated induction of SSAT and annexin approach will replace the traditional trial-and-error
II mRNA. mRNA levels of thymosin-b-10, MAT-8, and practice of cancer medicine.
chaperonin-10 were unchanged in the p53-null setting.
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