Activation of pim kinases is sufficient to promote resistance to MET small-molecule inhibitors

Ningfei An, Ying Xiong, Amanda C. LaRue, Andrew S. Kraft, Bo Cen

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Mesenchymal-epithelial transition (MET) blockade offers a new targeted therapy particularly in those cancers with MET amplification. However, the efficacy and the duration of the response to MET inhibitors are limited by the emergence of drug resistance. Here, we report that resistance to small-molecule inhibitors of MET can arise from increased expression of the prosurvival Pim protein kinases. This resistance mechanism was documented in non-small cell lung cancer and gastric cancer cells with MET amplification. Inhibition of Pim kinases enhanced cell death triggered by short-term treatment with MET inhibitors. Pim kinases control the translation of anti-apoptotic protein Bcl-2 at an internal ribosome entry site and this mechanism was identified as the basis for Pim-mediated resistance to MET inhibitors. Protein synthesis was increased in drug-resistant cells, secondary to a Pim-mediated increase in cap-independent translation. In cells rendered drug resistant by chronic treatment with MET inhibitors, genetic or pharmacologic inhibition of Pim kinases was sufficient to restore sensitivity in vitro and in vivo. Taken together, our results rationalize Pim inhibition as a strategy to augment responses and blunt acquired resistance to MET inhibitors in cancer.

Original languageEnglish (US)
Pages (from-to)5318-5328
Number of pages11
JournalCancer Research
Volume75
Issue number24
DOIs
StatePublished - Dec 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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