RASA1 and NF1 co-mutated non-small cell lung carcinomas: Cancer genomic data and evaluation of sensitivity to MEK inhibition.

Abstract

11600 Background: Ras-GTPase activating proteins (RasGAPs), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. While NF1 mutations are enriched in non-small cell lung carcinomas (NSCLC) lacking KRAS alterations, they are not completely mutually exclusive. We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases. Methods: Large genomic datasets of NSCLC [MSK-IMPACT™ dataset at MSKCC (n = 2004), TCGA combined lung cancer dataset (n = 1144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBECs) and NSCLC lines with RasGAP truncating mutations, in RASA1 (RERFLCKJ), NF1 (LCLC103H and H1838), or both (EPLC272H). Results: Overall, approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (p = .02) and KRAS (p = .02) mutations. Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p < .001), suggesting selection for loss of more than one RasGAP. Furthermore, all patients (16/16) with concurrent RASA1/NF1 truncating mutations lacked other known lung cancer drivers, including KRAS. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RERFLCKJ cells reduced MAPK and PI3K signaling. While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK (trametinib) or PI3K (GDC0941, PI103), EPLC272H cells (with concurrent RASA1/NF1 mutations) showed notably more profound sensitivity (IC50: 0.040µM trametinib). Finally, simultaneous silencing of RASA1 and NF1 sensitized both HBECs and NSCLC cells to MEK inhibition. Conclusions: Cancer genomic and functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC. Patients whose tumors show this distinctive genotype should be considered for trials of MEK inhibitors.