Identification and Characterization of Oncogenic Mutations in Lung Adenocarcinoma

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 , 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 induces anchorage-independent cell growth and tumor formation . 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 for survival and is also sensitive to MEK inhibition. Our work provides experimental evidence for the role of as an oncogene and suggests a possible therapeutic strategy to target -mutated cancers. IMPLICATIONS: This study demonstrates that mutations found in lung adenocarcinoma are oncogenic and that MEK inhibition may be a therapeutic avenue for the treatment of -mutant cancers.