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
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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 AACR. See related commentary by Kitajima and Barbie, p. 1243
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In some LUAD and LUSC, NF1 and RASA1 co-mutations create dependence on MEK-ERK signaling and greater sensitivity to MEK inhibitors.
“co-mutations in NF1 and RASA1, encoding two critical RAS pathway GTPase-activating proteins (GAPs), drive addiction to the MEK–ERK signaling axis and confer enhanced sensitivity to MEK inhibitors in a subset of both LUAD and LUSC171, 172.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [172]
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Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
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<i>RASA1</i>/<i>NF1</i>-Mutant Lung Cancer: Racing to the Clinic?
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- Authors
- Hayashi, T., Desmeules, P., Smith, R. S., Drilon, A., Somwar, R., & Ladanyi, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Venue
- Clinical Cancer Research
- Published
- 2018-03-14
- Volume
- 24
- Issue
- 6
- Pages
- 1436-1447
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC6440215
- OpenAlex
- W2767780132
- Cited by
- 90
- References
- 41
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 30 · 2022: 4 · 2021: 10 · 2020: 9 · 2019: 13 · 2018: 6
- FWCI
- 6.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA129243, P30CA008748)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- RASA1, neurofibromatosis type 1, non-small cell lung cancer, Ras GTPase-activating protein, RAS/MAPK pathway, MEK inhibition, trametinib, co-occurring mutations, smoking, EGFR, KRAS, PI3K signaling, drug sensitivity, loss-of-function mutations, bronchial epithelial cells, tumor suppressor
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Cell Survival, Cell Transformation, Neoplastic, Humans, Lung Neoplasms, Mutation, Smoking, Signal Transduction, Gene Expression Regulation, Neoplastic, Apoptosis, p120 GTPase Activating Protein, Neurofibromin 1, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Cell Cycle Checkpoints
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