title: RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer.
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.
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Gorjan
authors: G
authors: Hrustanovic
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Victor
authors: V
authors: Olivas
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Evangelos
authors: http://orcid.org/0000-0002-5453-1646
authors: E
authors: Pazarentzos
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Asmin
authors: A
authors: Tulpule
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Saurabh
authors: S
authors: Asthana
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Collin M
authors: CM
authors: Blakely
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Ross A
authors: RA
authors: Okimoto
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Luping
authors: L
authors: Lin
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Dana S
authors: DS
authors: Neel
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Amit
authors: A
authors: Sabnis
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Jennifer
authors: J
authors: Flanagan
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Elton
authors: E
authors: Chan
authors: Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA.|Department of Pathology, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA.
authors: Marileila
authors: M
authors: Varella-Garcia
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA.
authors: Dara L
authors: DL
authors: Aisner
authors: Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA.
authors: Aria
authors: A
authors: Vaishnavi
authors: Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, California, USA.|Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA.
authors: Sai-Hong I
authors: SH
authors: Ou
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Eric A
authors: EA
authors: Collisson
authors: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Eiki
authors: E
authors: Ichihara
authors: University of California Davis School of Medicine.|Comprehensive Cancer Center, Sacramento, California, USA.
authors: Philip C
authors: PC
authors: Mack
authors: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Christine M
authors: CM
authors: Lovly
authors: Cancer Biology and Precision Medicine Program Catalan Institute of Oncology Hospital Germans Trias i Pujol Badalona, Barcelona, Spain.
authors: Niki
authors: N
authors: Karachaliou
authors: Cancer Biology and Precision Medicine Program Catalan Institute of Oncology Hospital Germans Trias i Pujol Badalona, Barcelona, Spain.
authors: Rafael
authors: R
authors: Rosell
authors: University of California Davis School of Medicine.|Comprehensive Cancer Center, Sacramento, California, USA.
authors: Jonathan W
authors: JW
authors: Riess
authors: Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA.
authors: Robert C
authors: RC
authors: Doebele
authors: Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors: Trever G
authors: TG
authors: Bivona
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D054642:Dual Specificity Phosphatase 6 / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C522504:EML4-ALK fusion protein, human; C117307:KRAS protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins