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Mol Cancer Res DOI:10.1158/1541-7786.MCR-18-0316

Identification and characterization of oncogenic SOS1 mutations in lung adenocarcinoma.

Publication TypeJournal Article
Year of Publication2019
AuthorsCai, D, Choi, PS, Gelbard, M, Meyerson, M
JournalMol Cancer Res
Date Published2019 Jan 11
ISSN1557-3125
Abstract

Lung adenocarcinomas are characterized by mutations in the receptor tyrosine kinase (RTK)/Ras/Raf pathway, with up to 75% of cases containing mutations in known driver genes. However, the driver alterations in the remaining cases are yet to be determined. Recent exome sequencing analysis has identified SOS1, encoding a guanine nucleotide exchange factor, as significantly mutated in lung adenocarcinomas lacking canonical oncogenic RTK/Ras/Raf pathway mutations. Here, we demonstrate that ectopic expression of lung adenocarcinoma-derived mutants of SOS1 induces anchorage-independent cell growth in vitro and tumor formation in vivo. Biochemical experiments suggest that these mutations lead to over-activation of the Ras pathway, which can be suppressed by mutations that disrupt either the Ras-GEF or putative Rac-GEF activity of SOS1. Transcriptional profiling reveals that the expression of mutant SOS1 leads to the upregulation of MYC target genes and genes associated with Ras transformation. Furthermore, we demonstrate that an AML cancer cell line harboring a lung adenocarcinoma-associated mutant SOS1 is dependent on SOS1 for survival and is also sensitive to MEK inhibition. Our work provides experimental evidence for the role of SOS1 as an oncogene and suggests a possible therapeutic strategy to target SOS1-mutated cancers. Implications: This study demonstrates that SOS1 mutations found in lung adenocarcinoma are oncogenic and that MEK inhibition may be a therapeutic avenue for the treatment of SOS1-mutant cancers.

DOI10.1158/1541-7786.MCR-18-0316
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30635434?dopt=Abstract

Alternate JournalMol. Cancer Res.
PubMed ID30635434