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Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition.


ABSTRACT: The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors.We investigated the molecular factors and pathway activation signatures that determine sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells, and established cell line-derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor volume measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo.We found that HGF coexpression is a key predictor of response to c-MET inhibition among the examined factors and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET inhibition in responsive and nonresponsive cells. Surprisingly, we also found that short pretreatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the antitumor effects of c-MET inhibition. We observed a similar ligand-induced sensitization effect to an EGF receptor small-molecule kinase inhibitor.These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition and propose ligand pretreatment as a potential new strategy for improving the anticancer efficacy of RTK inhibitors.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC3602223 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition.

Zhang Ying Y   Farenholtz Kaitlyn E KE   Yang Yanzhi Y   Guessous Fadila F   Dipierro Charles G CG   Calvert Valerie S VS   Deng Jianghong J   Schiff David D   Xin Wenjun W   Lee Jae K JK   Purow Benjamin B   Christensen James J   Petricoin Emanuel E   Abounader Roger R  

Clinical cancer research : an official journal of the American Association for Cancer Research 20130205 6


<h4>Purpose</h4>The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors.<h4>Experimental design</h4>We investigate  ...[more]

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