Identification and Characterization of Oncogenic SOS1 Mutations in Lung Adenocarcinoma

Mol Cancer Res. 2019 Apr;17(4):1002-1012. doi: 10.1158/1541-7786.MCR-18-0316. Epub 2019 Jan 11.

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 overactivation 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / genetics*
  • Adenocarcinoma of Lung / metabolism
  • Adenocarcinoma of Lung / pathology
  • Animals
  • Gene Expression Profiling
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mutation
  • NIH 3T3 Cells
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • SOS1 Protein / genetics*
  • SOS1 Protein / metabolism
  • Transfection
  • Up-Regulation
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • SOS1 Protein
  • SOS1 protein, human
  • ras Proteins