Oncogenic RIT1 mutations in lung adenocarcinoma.
Lung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic mutations in RTK/RAS pathway members KRAS, EGFR, BRAF and ERBB2, and translocations involving ALK, RET and ROS1. Identification of these oncogenic events has transformed the treatment of lung adenocarcinoma via application of therapies targeted toward specific genetic lesions in stratified patient populations. However, such mutations have been reported in only ∼55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy are involved in the remaining cases. Here we report somatic mutations in the small GTPase gene RIT1 in ∼2% of lung adenocarcinoma cases that cluster in a hotspot near the switch II domain of the protein. RIT1 switch II domain mutations are mutually exclusive with all other known lung adenocarcinoma driver mutations. Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo, which can be reversed by combined PI3K and MEK inhibition. These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors.
1] Cancer Program, The Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, MA, USA [2] Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
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AH
Berger
1] Cancer Program, The Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, MA, USA [2] Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA [3] Department of Pathology, Massachusetts General Hospital, Boston, MA, USA [4] Department of Pathology, Harvard Medical School, Boston, MA, USA.
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Imielinski
Cancer Program, The Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, MA, USA.
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Duke
1] Cancer Program, The Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, MA, USA [2] Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA [3] Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
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Wala
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
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Kaplan
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA.
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Shi
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA.
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DA
Andres
1] Cancer Program, The Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, MA, USA [2] Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA [3] Department of Pathology, Harvard Medical School, Boston, MA, USA.
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Meyerson
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental; D016716:PC12 Cells; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014481:United States; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins; C486776:RIT1 protein, human; D018631:ras Proteins