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Cancer Discov. 2016 Jul;6(7):754-69. doi: 10.1158/2159-8290.CD-15-1377. Epub 2016 May 6.

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

Author information

1
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan. First Department of Medicine, Hokkaido University School of Medicine, Hokkaido, Japan.
2
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan. Institute for Frontier Science Initiative, Kanazawa University, Ishikawa, Japan. hebi@staff.kanazawa-u.ac.jp syano@staff.kanazawa-u.ac.jp.
3
Department of Biobank, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
4
VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
5
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan.
6
First Department of Medicine, Hokkaido University School of Medicine, Hokkaido, Japan.
7
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan. hebi@staff.kanazawa-u.ac.jp syano@staff.kanazawa-u.ac.jp.

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

PMID:
27154822
PMCID:
PMC4957999
DOI:
10.1158/2159-8290.CD-15-1377
[Indexed for MEDLINE]
Free PMC Article

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