Journal
CANCER DISCOVERY
Volume 6, Issue 7, Pages 754-769Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-15-1377
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Funding
- Scientific Research on Innovative Areas Integrative Research on Cancer Microenvironment Network [22112010A01]
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan
- AstraZeneca RD Grant Award
- Kobayashi Foundation for Cancer Research
- NCI Transition Career Development Award [K22CA175276]
- American Lung Association Lung Cancer Discovery Award
- George and Lavinia Blick Research Fund
- [26830105]
- [21390256]
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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. (C) 2016 AACR.
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