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Nat Med. 2015 Sep;21(9):1038-47. doi: 10.1038/nm.3930. Epub 2015 Aug 24.

RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer.

Author information

1
Department of Medicine, University of California at San Francisco, San Francisco, California, USA.
2
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
3
Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA.
4
Department of Pathology, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA.
5
Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, California, USA.
6
Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
7
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
8
University of California Davis School of Medicine.
9
Comprehensive Cancer Center, Sacramento, California, USA.
10
Cancer Biology and Precision Medicine Program Catalan Institute of Oncology Hospital Germans Trias i Pujol Badalona, Barcelona, Spain.

Abstract

One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.

PMID:
26301689
PMCID:
PMC4734742
DOI:
10.1038/nm.3930
[Indexed for MEDLINE]
Free PMC Article

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