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

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.

• Authors: Aijun Shen, Lu Wang, Min Huang, Jingya Sun, Yi Chen, Yan-Yan Shen, Xinying Yang, Xin Wang, Jian Ding, Meiyu Geng
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 21 Pg. 4548-59 (Nov 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26483207 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• 6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline
• MYC protein, human
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-myc
• Pyridazines
• Quinazolines
• RNA, Small Interfering
• Triazoles
• Proto-Oncogene Proteins c-met
• Gefitinib

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (genetics)
• Drug Resistance, Neoplasm (genetics)
• Gefitinib
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Targeted Therapy
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-myc (antagonists & inhibitors, genetics)
• Pyridazines (pharmacology)
• Quinazolines (pharmacology)
• RNA Interference
• RNA, Small Interfering
• Triazoles (pharmacology)
• Xenograft Model Antitumor Assays