Journal
NATURE MEDICINE
Volume 21, Issue 9, Pages 1038-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/nm.3930
Keywords
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Funding
- US National Institute of Health (NIH) Director's New Innovator Award
- Howard Hughes Medical Institute
- Doris Duke Charitable Foundation
- American Lung Association
- National Lung Cancer Partnership
- Sidney Kimmel Foundation for Cancer Research
- Searle Scholars Program
- UCSF Clinical and Translational Science Institute
- National Cancer Institute (NCI) of the NIH [R01CA121210, P01CA129243]
- Damon Runyon Clinical Investigator Award
- LUNGevity Career Development Award
- NIH [NCI5K12CA086913, NCI-P30CA046934]
- NIH Paul Calabresi Cancer Development Award in Clinical Oncology [K12CA138464]
- Lung Cancer SPORE [NCI-P50CA058187]
- La Caixa Foundation
- Redes Tematicas de Investigacion en Cancer [RD12/0036/0072]
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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.
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