1. Academic Validation
  2. c-Myc alterations confer therapeutic response and acquired resistance to c-Met inhibitors in MET-addicted cancers

c-Myc alterations confer therapeutic response and acquired resistance to c-Met inhibitors in MET-addicted cancers

  • Cancer Res. 2015 Nov 1;75(21):4548-59. doi: 10.1158/0008-5472.CAN-14-2743.
Aijun Shen 1 Lu Wang 1 Min Huang 1 Jingya Sun 1 Yi Chen 1 Yan-Yan Shen 1 Xinying Yang 1 Xin Wang 1 Jian Ding 2 Meiyu Geng 2
Affiliations

Affiliations

  • 1 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai China. mygeng@simm.ac.cn jding@simm.ac.cn.
Abstract

Use of kinase inhibitors in Cancer therapy leads invariably to acquired resistance stemming from kinase reprogramming. To overcome the dynamic nature of kinase adaptation, we asked whether a signal-integrating downstream effector might exist that provides a more applicable therapeutic target. In this study, we reported that the transcriptional factor c-Myc functions as a downstream effector to dictate the therapeutic response to c-Met inhibitors in c-Met-addicted Cancer and derived resistance. Dissociation of c-Myc from c-Met control, likely overtaken by a variety of reprogrammed kinases, led to acquisition of drug resistance. Notably, c-Myc blockade by RNA interference or pharmacologic inhibition circumvented the acquired resistance to c-Met inhibition. Combining c-Myc blockade and c-Met inhibition in MET-amplified patient-derived xenograft mouse models heightened therapeutic activity. Our findings offer a preclinical proof of concept for the application of c-Myc-blocking agents as a tactic to thwart resistance to kinase inhibitors.

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