title: Characteristics of lung cancers harboring NRAS mutations.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Vanderbilt-Ingram Cancer Center, Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Kadoaki
authors.initials: K
authors.lastname: Ohashi
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Teresa
authors.initials: T
authors.lastname: Moran
authors.forename: David Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Vnencak-Jones
authors.forename: Lynne
authors.initials: L
authors.lastname: Berry
authors.forename: Yumei
authors.initials: Y
authors.lastname: Pan
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Sasaki
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Edward B
authors.initials: EB
authors.lastname: Garon
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Martin L
authors.initials: ML
authors.lastname: Sos
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C117307:KRAS protein, human; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins