and are Preferentially Co-Mutated and Define A Distinct Genetic Subset of Smoking-Associated Non-Small Cell Lung Carcinomas Sensitive to MEK Inhibition.

Ras-GTPase-activating proteins (RasGAP), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. We evaluated clinical and molecular characteristics of non-small cell lung carcinoma (NSCLC) with mutations in comparison with -mutated cases. Large genomic datasets of NSCLC [MSK-IMPACT dataset at MSKCC ( = 2,004), TCGA combined lung cancer dataset ( = 1,144)] were analyzed to define concurrent mutations and clinical features of -mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBEC) and NSCLC lines with truncating mutations in , or both. Overall, approximately 2% of NSCLCs had -truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating ( = 0.02) and ( = 0.02) mutations. Unexpectedly, -truncating mutations had a strong tendency to co-occur with -truncating mutations ( < 0.001). Furthermore, all patients (16/16) with concurrent -truncating mutations lacked other known lung cancer drivers. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in -mutated cells reduced MAPK and PI3K signaling. Although growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent mutations were profoundly more sensitive (IC: 0.040 μmol/L trametinib). Finally, simultaneous genetic silencing of and sensitized both HBECs and NSCLC cells to MEK inhibition. Cancer genomic and functional data nominate concurrent loss-of-function mutations as a strong mitogenic driver in NSCLC, which may sensitize to trametinib. .