Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to ... more Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited. Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK-inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistanc...
The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting... more The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells. We further demonstrate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred by MYCN upregulation in vitro and in vivo. Together, combined inhibition of ALK and MDM2 may provide an effective ...
Physiologic elevation of insulin levels induces a significant increase in muscle adenosine tripho... more Physiologic elevation of insulin levels induces a significant increase in muscle adenosine triphosphate (ATP) synthesis rate in normal individuals, indicative of an appropriate acceleration in mitochondrial activity. However, the stimulatory effect of insulin is diminished in insulin-resistant patients. In the absence of similar data from preclinical models, the present study investigated the inhibitory effects of increased dietary fat intake on insulin-stimulated ATP synthesis rates in rats. After being placed on a high-fat diet for 8 weeks (n = 10), diet-induced obese male Sprague-Dawley rats were tested against age-matched control rats (n = 9) on a normal chow diet. Muscle ATP synthase flux rates were measured under anesthesia by in vivo (31)P saturation transfer both before and during a euglycemic-hyperinsulinemic clamp. The glucose infusion rates observed during the clamp revealed impaired peripheral insulin sensitivity in the high-fat-fed rats when compared with the age-matched control rats. Under baseline conditions (ie, low insulin), the muscle ATP synthesis rates of high-fat-fed rats were approximately 30% lower (P < .05) than those in chow-fed rats. Moreover, chow-fed animals showed a significant increase (25%, P < .05 vs basal) in muscle ATP synthesis activity upon insulin stimulation, whereas high-fat-fed animals displayed no substantial change. These data demonstrated for the first time in a preclinical model that the insulin challenge not only facilitates an improvement in the dynamic range of ATP turnover measurement by (31)P saturation transfer between normal and insulin-resistant rats, but also mimics challenge that is relevant for pharmacologic studies on antidiabetic drugs aimed at improving mitochondrial function.
Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is ... more Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alphaK(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.
Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carci... more Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance, we have observed that SCC cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance.
Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to ... more Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited. Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK-inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistanc...
The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting... more The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells. We further demonstrate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred by MYCN upregulation in vitro and in vivo. Together, combined inhibition of ALK and MDM2 may provide an effective ...
Physiologic elevation of insulin levels induces a significant increase in muscle adenosine tripho... more Physiologic elevation of insulin levels induces a significant increase in muscle adenosine triphosphate (ATP) synthesis rate in normal individuals, indicative of an appropriate acceleration in mitochondrial activity. However, the stimulatory effect of insulin is diminished in insulin-resistant patients. In the absence of similar data from preclinical models, the present study investigated the inhibitory effects of increased dietary fat intake on insulin-stimulated ATP synthesis rates in rats. After being placed on a high-fat diet for 8 weeks (n = 10), diet-induced obese male Sprague-Dawley rats were tested against age-matched control rats (n = 9) on a normal chow diet. Muscle ATP synthase flux rates were measured under anesthesia by in vivo (31)P saturation transfer both before and during a euglycemic-hyperinsulinemic clamp. The glucose infusion rates observed during the clamp revealed impaired peripheral insulin sensitivity in the high-fat-fed rats when compared with the age-matched control rats. Under baseline conditions (ie, low insulin), the muscle ATP synthesis rates of high-fat-fed rats were approximately 30% lower (P < .05) than those in chow-fed rats. Moreover, chow-fed animals showed a significant increase (25%, P < .05 vs basal) in muscle ATP synthesis activity upon insulin stimulation, whereas high-fat-fed animals displayed no substantial change. These data demonstrated for the first time in a preclinical model that the insulin challenge not only facilitates an improvement in the dynamic range of ATP turnover measurement by (31)P saturation transfer between normal and insulin-resistant rats, but also mimics challenge that is relevant for pharmacologic studies on antidiabetic drugs aimed at improving mitochondrial function.
Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is ... more Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alphaK(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.
Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carci... more Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance, we have observed that SCC cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance.
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Papers by Jinsheng Liang