Oncogenic RIT1 mutations in lung adenocarcinoma

A. H. Berger, M. Imielinski, F. Duke, J. Wala, N. Kaplan, G. X. Shi, D. A. Andres, M. Meyerson

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4418-4423
Number of pages6
JournalOncogene
Volume33
Issue number35
DOIs
StatePublished - 2014

Bibliographical note

Funding Information:
We thank A. Brooks, P. Choi, H. Gannon, H. Greulich, L. De Waal, B. Kaplan, R. Liao, T. Sharifnia, J. Boehm and A. Koehler for critical advice and discussion. AHB is supported by a postdoctoral fellowship from the American Cancer Society. MI is supported by NCI Training Grant T32CA9216. JW is supported by NIH Training Grant T32HG002295. DAA is supported by NIH NS045103, KSCHIRT 12-1A, and a University of Kentucky Research Professorship. This work was supported by grants from the Department of Defense (#W81XWH-12-1-0269) National Cancer Institute (P01CA154303 and R01CA109038), Uniting Against Lung Cancer, the Lung Cancer Research Foundation and the American Lung Association to MM.

Keywords

  • GTPase
  • RAS pathway
  • cancer genetics
  • lung adenocarcinoma
  • oncogene
  • signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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