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

Gorjan Hrustanovic, Victor Olivas, Evangelos Pazarentzos, Asmin Tulpule, Saurabh Asthana, Collin M. Blakely, Ross A. Okimoto, Luping Lin, Dana S. Neel, Amit Sabnis, Jennifer Flanagan, Elton Chan, Marileila Varella-Garcia, Dara L. Aisner, Aria Vaishnavi, Sai Hong I Ou, Eric A. Collisson, Eiki Ichihara, Philip Mack, Christine M. LovlyNiki Karachaliou, Rafael Rosell, Jonathan Riess, Robert C. Doebele, Trever G. Bivona

Research output: Contribution to journalArticle

122 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1038-1047
Number of pages10
JournalNature Medicine
Volume21
Issue number9
DOIs
StatePublished - Sep 8 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Hrustanovic, G., Olivas, V., Pazarentzos, E., Tulpule, A., Asthana, S., Blakely, C. M., Okimoto, R. A., Lin, L., Neel, D. S., Sabnis, A., Flanagan, J., Chan, E., Varella-Garcia, M., Aisner, D. L., Vaishnavi, A., Ou, S. H. I., Collisson, E. A., Ichihara, E., Mack, P., ... Bivona, T. G. (2015). RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nature Medicine, 21(9), 1038-1047. https://doi.org/10.1038/nm.3930