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 C. Mack, Christine M. LovlyNiki Karachaliou, Rafael Rosell, Jonathan W. Riess, Robert C. Doebele, Trever G. Bivona

Research output: Contribution to journalArticle

111 Citations (Scopus)

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
Pages (from-to)1038-1047
Number of pages10
JournalNature Medicine
Volume21
Issue number9
DOIs
Publication statusPublished - Sep 8 2015
Externally publishedYes

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Mitogen-Activated Protein Kinases
Lung Neoplasms
Tumors
Mitogen-Activated Protein Kinase Phosphatases
Cells
MAP Kinase Kinase Kinases
Neoplasms
Gene encoding
Gene Dosage
GTP Phosphohydrolases
Mitogen-Activated Protein Kinase Kinases
Drug Resistance
Cell Survival
Protein Isoforms
Fusion reactions
Survival
Adenocarcinoma of lung
Pharmaceutical Preparations

ASJC Scopus subject areas

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

Cite this

Hrustanovic, G., Olivas, V., Pazarentzos, E., Tulpule, A., Asthana, S., Blakely, C. M., ... 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

RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. / Hrustanovic, Gorjan; Olivas, Victor; Pazarentzos, Evangelos; Tulpule, Asmin; Asthana, Saurabh; Blakely, Collin M.; Okimoto, Ross A.; Lin, Luping; Neel, Dana S.; Sabnis, Amit; Flanagan, Jennifer; Chan, Elton; Varella-Garcia, Marileila; Aisner, Dara L.; Vaishnavi, Aria; Ou, Sai Hong I; Collisson, Eric A.; Ichihara, Eiki; Mack, Philip C.; Lovly, Christine M.; Karachaliou, Niki; Rosell, Rafael; Riess, Jonathan W.; Doebele, Robert C.; Bivona, Trever G.

In: Nature Medicine, Vol. 21, No. 9, 08.09.2015, p. 1038-1047.

Research output: Contribution to journalArticle

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, SHI, Collisson, EA, Ichihara, E, Mack, PC, Lovly, CM, Karachaliou, N, Rosell, R, Riess, JW, Doebele, RC & Bivona, TG 2015, 'RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer', Nature Medicine, vol. 21, no. 9, pp. 1038-1047. https://doi.org/10.1038/nm.3930
Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S, Blakely CM et al. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nature Medicine. 2015 Sep 8;21(9):1038-1047. https://doi.org/10.1038/nm.3930
Hrustanovic, Gorjan ; Olivas, Victor ; Pazarentzos, Evangelos ; Tulpule, Asmin ; Asthana, Saurabh ; Blakely, Collin M. ; Okimoto, Ross A. ; Lin, Luping ; Neel, Dana S. ; Sabnis, Amit ; Flanagan, Jennifer ; Chan, Elton ; Varella-Garcia, Marileila ; Aisner, Dara L. ; Vaishnavi, Aria ; Ou, Sai Hong I ; Collisson, Eric A. ; Ichihara, Eiki ; Mack, Philip C. ; Lovly, Christine M. ; Karachaliou, Niki ; Rosell, Rafael ; Riess, Jonathan W. ; Doebele, Robert C. ; Bivona, Trever G. / RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. In: Nature Medicine. 2015 ; Vol. 21, No. 9. pp. 1038-1047.
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