Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer

Hidenori Kitai, Hiromichi Ebi, Shuta Tomida, Konstantinos V. Floros, Hiroshi Kotani, Yuta Adachi, Satoshi Oizumi, Masaharu Nishimura, Anthony C. Faber, Seiji Yano

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS -mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS -mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo. These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS -mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors. SIGNIFICANCE: Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS -mutant non–small cell lung cancer (NSCLC). In mesenchymal-like KRAS -mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage.

Original languageEnglish
Pages (from-to)754-769
Number of pages16
JournalCancer discovery
Volume6
Issue number7
DOIs
Publication statusPublished - Jul 2016

ASJC Scopus subject areas

  • Oncology

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