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

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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 1 2016

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Epithelial-Mesenchymal Transition
Mitogen-Activated Protein Kinase Kinases
Receptor Protein-Tyrosine Kinases
Lung Neoplasms
Non-Small Cell Lung Carcinoma
Neoplasms
Cell Death

ASJC Scopus subject areas

  • Oncology

Cite this

Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer. / Kitai, Hidenori; Ebi, Hiromichi; Tomida, Shuta; Floros, Konstantinos V.; Kotani, Hiroshi; Adachi, Yuta; Oizumi, Satoshi; Nishimura, Masaharu; Faber, Anthony C.; Yano, Seiji.

In: Cancer Discovery, Vol. 6, No. 7, 01.07.2016, p. 754-769.

Research output: Contribution to journalArticle

Kitai, Hidenori ; Ebi, Hiromichi ; Tomida, Shuta ; Floros, Konstantinos V. ; Kotani, Hiroshi ; Adachi, Yuta ; Oizumi, Satoshi ; Nishimura, Masaharu ; Faber, Anthony C. ; Yano, Seiji. / Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer. In: Cancer Discovery. 2016 ; Vol. 6, No. 7. pp. 754-769.
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