Characteristics of lung cancers harboring NRAS mutations Journal Article
| Authors: | Ohashi, K.; Sequist, L. V.; Arcila, M. E.; Lovly, C. M.; Chen, X.; Rudin, C. M.; Moran, T.; Camidge, D. R.; Vnencak-Jones, C. L.; Berry, L.; Pan, Y.; Sasaki, H.; Engelman, J. A.; Garon, E. B.; Dubinett, S. M.; Franklin, W. A.; Riely, G. J.; Sos, M. L.; Kris, M. G.; Dias-Santagata, D.; Ladanyi, M.; Bunn, P. A. Jr; Pao, W. |
| Article Title: | Characteristics of lung cancers harboring NRAS mutations |
| Abstract: | Purpose: We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS-mutant lung cancer cells. Experimental Design: We reviewed clinical data from patients whose lung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations. Six NRAS-mutant cell lines were screened for sensitivity against inhibitors of multiple kinases (i.e., EGFR, ALK, MET, IGF-1R, BRAF, PI3K, and MEK). Results: Among 4,562 patients with lung cancers tested, NRAS mutations were present in 30 (0.7%; 95% confidence interval, 0.45%-0.94%); 28 of these had no other driver mutations. 83% had adenocarcinoma histology with no significant differences in gender. While 95% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS-mutated lung tumors than KRAS-mutant non-small cell lung cancer [NSCLC; NRAS: 13% (4/30), KRAS: 66% (1772/2733), P < 0.00000001]. Five of 6 NRAS-mutant cell lines were sensitive to the MEK inhibitors, selumetinib and trametinib, but not to other inhibitors tested. Conclusion: NRAS mutations define a distinct subset of lung cancers (∼1%) with potential sensitivity to MEK inhibitors. Although NRAS mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking. ©2013 AACR. |
| Keywords: | mitogen activated protein kinase; vasculotropin; adult; human tissue; aged; aged, 80 and over; middle aged; gene mutation; human cell; major clinical study; overall survival; somatic mutation; mutation, missense; proto-oncogene proteins; histopathology; erlotinib; antineoplastic agents; adenocarcinoma; gene; progression free survival; lung non small cell cancer; lung neoplasms; membrane proteins; genotype; gene frequency; lung cancer; smoking; cancer cell culture; in vitro study; cell line, tumor; pyridones; pyrimidinones; retrospective study; phosphatidylinositol 3 kinase; somatomedin c receptor; protein kinase inhibitors; lung adenocarcinoma; dna mutational analysis; ras proteins; oncogene k ras; inhibitory concentration 50; k ras protein; b raf kinase; benzimidazoles; gtp phosphohydrolases; nras gene; selumetinib; crizotinib; genetic association studies; trametinib; linsitinib |
| Journal Title: | Clinical Cancer Research |
| Volume: | 19 |
| Issue: | 9 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2013-05-01 |
| Start Page: | 2584 |
| End Page: | 2591 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-12-3173 |
| PROVIDER: | scopus |
| PMCID: | PMC3643999 |
| PUBMED: | 23515407 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 June 2013" - "CODEN: CCREF" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work