RASA1 and NF1 are Preferentially Co-Mutated and Define A Distinct Genetic Subset of Smoking-Associated Non-Small Cell Lung Carcinomas Sensitive to MEK Inhibition

Clin Cancer Res. 2018 Mar 15;24(6):1436-1447. doi: 10.1158/1078-0432.CCR-17-2343. Epub 2017 Nov 10.

Abstract

Purpose: 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 RASA1 mutations in comparison with NF1-mutated cases.Experimental Design: Large genomic datasets of NSCLC [MSK-IMPACT dataset at MSKCC (n = 2,004), TCGA combined lung cancer dataset (n = 1,144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBEC) and NSCLC lines with truncating mutations in RASA1, NF1, or both.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 = 0.02) and KRAS (P = 0.02) mutations. Unexpectedly, RASA1-truncating mutations had a strong tendency to co-occur with NF1-truncating mutations (P < 0.001). Furthermore, all patients (16/16) with concurrent RASA1/NF1-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 RASA1-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 RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040 μmol/L trametinib). Finally, simultaneous genetic 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, which may sensitize to trametinib. Clin Cancer Res; 24(6); 1436-47. ©2017 AACRSee related commentary by Kitajima and Barbie, p. 1243.

Publication types

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

MeSH terms

  • Apoptosis / drug effects
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / etiology*
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mutation*
  • Neurofibromin 1 / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction / drug effects
  • Smoking / adverse effects
  • p120 GTPase Activating Protein / genetics*

Substances

  • NF1 protein, human
  • Neurofibromin 1
  • Protein Kinase Inhibitors
  • RASA1 protein, human
  • p120 GTPase Activating Protein