Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer

• Published in: Cancer discovery 2016-07, Vol.6 (7), p.754-769
• Main Authors: Kitai, Hidenori, Ebi, Hiromichi, Tomida, Shuta, Floros, Konstantinos V, Kotani, Hiroshi, Adachi, Yuta, Oizumi, Satoshi, Nishimura, Masaharu, Faber, Anthony C, Yano, Seiji
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Cell Death - drug effects; Cell Line, Tumor; Cluster Analysis; Disease Models, Animal; Enzyme Activation; Epithelial-Mesenchymal Transition - genetics; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Gene Expression; Gene Expression Profiling; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Membrane Proteins - metabolism; Mice; Mutation; Nerve Tissue Proteins - metabolism; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; ras Proteins - genetics; Receptor, ErbB-3 - metabolism; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Receptors, Fibroblast Growth Factor - antagonists & inhibitors; Receptors, Fibroblast Growth Factor - metabolism; Signal Transduction - drug effects; Xenograft Model Antitumor Assays
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-15-1377

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. 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. Cancer Discov; 6(7); 754-69. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.