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

Abstract

KRAS is frequently mutated in lung cancer. Whereas the mitogen-activated protein kinase (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 de-repression of SPRY4 and subsequent FGFR1-mediated re-activation of MEK and AKT. Therapeutically, the combination of MEK inhibitor and FGFR inhibitor 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.