Characteristics of lung cancers harboring NRAS mutations

Kadoaki Oohashi, Lecia V. Sequist, Maria E. Arcila, Christine M. Lovly, Xi Chen, Charles M. Rudin, Teresa Moran, David Ross Camidge, Cindy L. Vnencak-Jones, Lynne Berry, Yumei Pan, Hidefumi Sasaki, Jeffrey A. Engelman, Edward B. Garon, Steven M. Dubinett, Wilbur A. Franklin, Gregory J. Riely, Martin L. Sos, Mark G. Kris, Dora Dias-SantagataMarc Ladanyi, Paul A. Bunn, William Pao

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2584-2591
Number of pages8
JournalClinical Cancer Research
Volume19
Issue number9
DOIs
Publication statusPublished - May 1 2013
Externally publishedYes

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Lung Neoplasms
Mutation
Mitogen-Activated Protein Kinase Kinases
Smoking
Cell Line
Phosphatidylinositol 3-Kinases
Non-Small Cell Lung Carcinoma
Neoplasms
Histology
Adenocarcinoma
Research Design
Phosphotransferases
Confidence Intervals
Lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Oohashi, K., Sequist, L. V., Arcila, M. E., Lovly, C. M., Chen, X., Rudin, C. M., ... Pao, W. (2013). Characteristics of lung cancers harboring NRAS mutations. Clinical Cancer Research, 19(9), 2584-2591. https://doi.org/10.1158/1078-0432.CCR-12-3173

Characteristics of lung cancers harboring NRAS mutations. / Oohashi, Kadoaki; Sequist, Lecia V.; Arcila, Maria E.; Lovly, Christine M.; Chen, Xi; Rudin, Charles M.; Moran, Teresa; Camidge, David Ross; Vnencak-Jones, Cindy L.; Berry, Lynne; Pan, Yumei; Sasaki, Hidefumi; Engelman, Jeffrey A.; Garon, Edward B.; Dubinett, Steven M.; Franklin, Wilbur A.; Riely, Gregory J.; Sos, Martin L.; Kris, Mark G.; Dias-Santagata, Dora; Ladanyi, Marc; Bunn, Paul A.; Pao, William.

In: Clinical Cancer Research, Vol. 19, No. 9, 01.05.2013, p. 2584-2591.

Research output: Contribution to journalArticle

Oohashi, K, Sequist, LV, Arcila, ME, Lovly, CM, Chen, X, Rudin, CM, Moran, T, Camidge, DR, Vnencak-Jones, CL, Berry, L, Pan, Y, Sasaki, H, Engelman, JA, Garon, EB, Dubinett, SM, Franklin, WA, Riely, GJ, Sos, ML, Kris, MG, Dias-Santagata, D, Ladanyi, M, Bunn, PA & Pao, W 2013, 'Characteristics of lung cancers harboring NRAS mutations', Clinical Cancer Research, vol. 19, no. 9, pp. 2584-2591. https://doi.org/10.1158/1078-0432.CCR-12-3173
Oohashi K, Sequist LV, Arcila ME, Lovly CM, Chen X, Rudin CM et al. Characteristics of lung cancers harboring NRAS mutations. Clinical Cancer Research. 2013 May 1;19(9):2584-2591. https://doi.org/10.1158/1078-0432.CCR-12-3173
Oohashi, Kadoaki ; Sequist, Lecia V. ; Arcila, Maria E. ; Lovly, Christine M. ; Chen, Xi ; Rudin, Charles M. ; Moran, Teresa ; Camidge, David Ross ; Vnencak-Jones, Cindy L. ; Berry, Lynne ; Pan, Yumei ; Sasaki, Hidefumi ; Engelman, Jeffrey A. ; Garon, Edward B. ; Dubinett, Steven M. ; Franklin, Wilbur A. ; Riely, Gregory J. ; Sos, Martin L. ; Kris, Mark G. ; Dias-Santagata, Dora ; Ladanyi, Marc ; Bunn, Paul A. ; Pao, William. / Characteristics of lung cancers harboring NRAS mutations. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 9. pp. 2584-2591.
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AU - Oohashi, Kadoaki

AU - Sequist, Lecia V.

AU - Arcila, Maria E.

AU - Lovly, Christine M.

AU - Chen, Xi

AU - Rudin, Charles M.

AU - Moran, Teresa

AU - Camidge, David Ross

AU - Vnencak-Jones, Cindy L.

AU - Berry, Lynne

AU - Pan, Yumei

AU - Sasaki, Hidefumi

AU - Engelman, Jeffrey A.

AU - Garon, Edward B.

AU - Dubinett, Steven M.

AU - Franklin, Wilbur A.

AU - Riely, Gregory J.

AU - Sos, Martin L.

AU - Kris, Mark G.

AU - Dias-Santagata, Dora

AU - Ladanyi, Marc

AU - Bunn, Paul A.

AU - Pao, William

PY - 2013/5/1

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N2 - 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.

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