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Oncogene DOI:10.1038/onc.2013.581

Oncogenic RIT1 mutations in lung adenocarcinoma.

Publication TypeJournal Article
Year of Publication2014
AuthorsBerger, AH, Imielinski, M, Duke, F, Wala, J, Kaplan, N, Shi, G-X, Andres, DA, Meyerson, M
JournalOncogene
Volume33
Issue35
Pages4418-23
Date Published2014 Aug 28
ISSN1476-5594
KeywordsAdenocarcinoma, Animals, Antineoplastic Agents, Biomarkers, Tumor, Cell Line, Tumor, Humans, Lung Neoplasms, MAP Kinase Signaling System, Mice, Mice, Nude, Mutation, Neoplasms, Experimental, NIH 3T3 Cells, PC12 Cells, Protein Structure, Tertiary, Proto-Oncogene Proteins, ras Proteins, Rats, United States, Xenograft Model Antitumor Assays
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.

URLhttp://dx.doi.org/10.1038/onc.2013.581
DOI10.1038/onc.2013.581
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24469055?dopt=Abstract

Alternate JournalOncogene
PubMed ID24469055
PubMed Central IDPMC4150988
Grant ListT32HG002295 / HG / NHGRI NIH HHS / United States
NS045103 / NS / NINDS NIH HHS / United States
T32CA9216 / CA / NCI NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
R01CA109038 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
R01 CA109038 / CA / NCI NIH HHS / United States
T32 CA009216 / CA / NCI NIH HHS / United States
P01CA154303 / CA / NCI NIH HHS / United States
R56 NS045103 / NS / NINDS NIH HHS / United States
U24 CA143867 / CA / NCI NIH HHS / United States
R01 NS045103 / NS / NINDS NIH HHS / United States