title: MEK targeting in N-RAS mutated metastatic melanoma.
abstract: BACKGROUND
  Gain of function mutations in B-RAF and N-RAS occur frequently in melanoma, leading to mitogen activating protein kinase (MAPK) pathway activation, and this pathway is the target of drugs in development. Our purpose was to study clinical characteristics of patients with mutations in this pathway and to determine activity of inhibitors of B-RAF and MEK in short term cultures grown from tumors of some of these patients.
  
  
  METHODS
  Clinical and pathologic data were collected retrospectively on melanoma patients tested for B-RAF and N-RAS mutations at the Yale Cancer Center and associations with survival were determined. We studied in vitro activity of the pan-RAF inhibitor, RAF265, and the MEK inhibitor, MEK162, in 22 melanoma short term cultures. We further characterized the effect of MEK inhibition on apoptosis and growth of melanoma cultures.
  
  
  RESULTS
  In a cohort of 144 metastatic melanoma patients we found that patients with N-RAS mutant melanoma had a worse prognosis. These patients were more likely to have brain metastases at the time of presentation with metastatic disease than their N-RAS-wild-type counterparts. All N-RAS mutant melanoma cultures tested in our study (n = 7) were sensitive to MEK inhibition 162. Exposure to MEK162 reduced ERK1/2 phosphorylation, and induced apoptosis. Clonogenic survival was significantly reduced in sensitive melanoma cell cultures.
  
  
  CONCLUSIONS
  The prognosis of patients with melanoma expressing constitutively active N-RAS is poor, consistent with studies performed at other institutions. N-RAS mutant melanoma cultures appear to be particularly sensitive to MEK162, supporting ongoing clinical trials with MEK162 in N-RAS mutated melanoma.
authors.forename: Jaykumar
authors.initials: J
authors.lastname: Thumar
authors.forename: David
authors.initials: D
authors.lastname: Shahbazian
authors.forename: Saadia A
authors.initials: SA
authors.lastname: Aziz
authors.forename: Lucia B
authors.initials: LB
authors.lastname: Jilaveanu
authors.affiliation: Section of Medical Oncology, Yale Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW213, New Haven, CT 06520, USA. harriet.kluger@yale.edu.
authors.forename: Harriet M
authors.initials: HM
authors.lastname: Kluger
mesh_terms: D000368:Aged; D001562:Benzimidazoles / Q000494:pharmacology; D015153:Blotting, Western; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C581313:binimetinib; D020930:MAP Kinase Kinase Kinases