Characteristics of Lung Cancers Harboring NRAS Mutations

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. Clin Cancer Res; 19(9); 2584–91. ©2013 AACR.

[1]  Robin Talbot,et al.  Analysis and interpretation of data , 2014 .

[2]  F. McCormick,et al.  Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling. , 2013, Cancer discovery.

[3]  Chandrani Chattopadhyay,et al.  Association of activated c‐Met with NRAS‐mutated human melanomas , 2012, International journal of cancer.

[4]  Carla Mattos,et al.  A comprehensive survey of Ras mutations in cancer. , 2012, Cancer research.

[5]  Yasushi Totoki,et al.  KIF5B-RET fusions in lung adenocarcinoma , 2012, Nature Medicine.

[6]  Yuki Togashi,et al.  RET, ROS1 and ALK fusions in lung cancer , 2012, Nature Medicine.

[7]  Doron Lipson,et al.  Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies , 2012, Nature Medicine.

[8]  D. Bar-Sagi,et al.  Sos-mediated cross activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis , 2012, Nature Communications.

[9]  William Pao,et al.  Lung Adenocarcinomas with HER2-Activating Mutations Are Associated with Distinct Clinical Features and HER2/EGFR Copy Number Gains , 2012, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[10]  A. Tsao,et al.  ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers , 2012 .

[11]  S. Digumarthy,et al.  Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  M. Ladanyi,et al.  Coexistence of PIK3CA and Other Oncogene Mutations in Lung Adenocarcinoma–Rationale for Comprehensive Mutation Profiling , 2011, Molecular Cancer Therapeutics.

[13]  A. Iafrate,et al.  Spectrum of Oncogenic Driver Mutations in Lung Adenocarcinomas from East Asian Never Smokers , 2011, PloS one.

[14]  D. Bar-Sagi,et al.  RAS oncogenes: weaving a tumorigenic web , 2011, Nature Reviews Cancer.

[15]  Jeffrey W. Clark,et al.  Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. , 2011, The Lancet. Oncology.

[16]  Antonio Marchetti,et al.  Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  M. Ladanyi,et al.  Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  N. Girard,et al.  New driver mutations in non-small-cell lung cancer. , 2011, The Lancet. Oncology.

[19]  A. Iafrate,et al.  A platform for rapid detection of multiple oncogenic mutations with relevance to targeted therapy in non-small-cell lung cancer. , 2011, The Journal of molecular diagnostics : JMD.

[20]  Jeffrey W. Clark,et al.  Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. , 2010, The New England journal of medicine.

[21]  A. Gemma,et al.  F1000 highlights , 2010 .

[22]  David N Louis,et al.  Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine , 2010, EMBO molecular medicine.

[23]  S. Toyooka,et al.  Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. , 2010, The Lancet. Oncology.

[24]  William Pao,et al.  Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer , 2009, Proceedings of the National Academy of Sciences.

[25]  William Pao,et al.  High Expression Levels of Total IGF-1R and Sensitivity of NSCLC Cells In Vitro to an Anti-IGF-1R Antibody (R1507) , 2009, PloS one.

[26]  Laura Tolosi,et al.  Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. , 2009, The Journal of clinical investigation.

[27]  William Pao,et al.  Genetic predictors of MEK dependence in non-small cell lung cancer. , 2008, Cancer research.

[28]  Brian H. Dunford-Shore,et al.  Somatic mutations affect key pathways in lung adenocarcinoma , 2008, Nature.

[29]  W. Lam,et al.  PIK3CA mutations and copy number gains in human lung cancers. , 2008, Cancer research.

[30]  Li Ding,et al.  Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. , 2008, Cancer research.

[31]  M. Ladanyi,et al.  Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma , 2008, Clinical Cancer Research.

[32]  A. Sweet-Cordero,et al.  Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon , 2008, Nature Genetics.

[33]  J. Settleman,et al.  Activated Kras, but Not Hras or Nras, May Initiate Tumors of Endodermal Origin via Stem Cell Expansion , 2008, Molecular and Cellular Biology.

[34]  H. Aburatani,et al.  Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer , 2007, Nature.

[35]  S. Gabriel,et al.  High-throughput oncogene mutation profiling in human cancer , 2007, Nature Genetics.

[36]  J. Minna,et al.  Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. , 2005, Cancer research.

[37]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[39]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[40]  J. Hancock,et al.  Ras proteins: different signals from different locations , 2003, Nature Reviews Molecular Cell Biology.

[41]  David Harrington,et al.  Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. , 2002, The New England journal of medicine.

[42]  D. Sidransky,et al.  Cigarette smoking is strongly associated with mutation of the K‐ras gene in patients with primary adenocarcinoma of the lung , 2001, Cancer.

[43]  M. Malumbres,et al.  Targeted Genomic Disruption of H-ras and N-ras, Individually or in Combination, Reveals the Dispensability of Both Loci for Mouse Growth and Development , 2001, Molecular and Cellular Biology.

[44]  P. Hainaut,et al.  Patterns of p53 G-->T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke. , 2001, Carcinogenesis.

[45]  S. Hecht,et al.  Tobacco smoke carcinogens and lung cancer. , 1999, Journal of the National Cancer Institute.

[46]  R. Kucherlapati,et al.  K-ras is an essential gene in the mouse with partial functional overlap with N-ras. , 1997, Genes & development.

[47]  T. Koh,et al.  N-ras mutation in 7,12-dimethylbenz[a]anthracene (DMBA)-induced erythroleukemia in Long-Evans rats. , 1995, Cancer letters.

[48]  M. Wigler,et al.  Three human transforming genes are related to the viral ras oncogenes. , 1983, Proceedings of the National Academy of Sciences of the United States of America.