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

Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S, Blakely CM, Okimoto RA, Lin L, Neel DS, Sabnis A, Flanagan J, Chan E, Varella-Garcia M, Aisner DL, Vaishnavi A, Ou SH, Collisson EA, Ichihara E, Mack PC, Lovly CM, Karachaliou N, Rosell R, Riess JW, Doebele RC, Bivona TG
Nat Med. 2015 21 (9): 1038-47

PMID: 26301689 · PMCID: PMC4734742 · DOI:10.1038/nm.3930

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.

MeSH Terms (13)

Anaplastic Lymphoma Kinase Cell Line, Tumor Drug Resistance, Neoplasm Dual Specificity Phosphatase 6 Humans Lung Neoplasms Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Oncogene Proteins, Fusion Proto-Oncogene Proteins Proto-Oncogene Proteins p21(ras) ras Proteins Receptor Protein-Tyrosine Kinases

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