title: Preexisting MEK1 exon 3 mutations in V600E/KBRAF melanomas do not confer resistance to BRAF inhibitors.
abstract: BRAF inhibitors (BRAFi) induce antitumor responses in nearly 60% of patients with advanced V600E/KBRAF melanomas. Somatic activating MEK1 mutations are thought to be rare in melanomas, but their potential concurrence with V600E/KBRAF may be selected for by BRAFi. We sequenced MEK1/2 exon 3 in melanomas at baseline and upon disease progression. Of 31 baseline V600E/KBRAF melanomas, 5 (16%) carried concurrent somatic BRAF/MEK1 activating mutations. Three of 5 patients with BRAF/MEK1 double-mutant baseline melanomas showed objective tumor responses, consistent with the overall 60% frequency. No MEK1 mutation was found in disease progression melanomas, except when it was already identified at baseline. MEK1-mutant expression in V600E/KBRAF melanoma cell lines resulted in no significant alterations in p-ERK1/2 levels or growth-inhibitory sensitivities to BRAFi, MEK1/2 inhibitor (MEKi), or their combination. Thus, activating MEK1 exon 3 mutations identified herein and concurrent with V600E/KBRAF do not cause BRAFi resistance in melanoma.
  
  
  CONCLUSIONS
  As BRAF inhibitors gain widespread use for treatment of advanced melanoma, biomarkers for drug sensitivity or resistance are urgently needed. We identify here concurrent activating mutations in BRAF and MEK1 in melanomas and show that the presence of a downstream mutation in MEK1 does not necessarily make BRAF–mutant melanomas resistant to BRAF inhibitors.
authors.affiliation: Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1750, USA.
authors.forename: Hubing
authors.initials: H
authors.lastname: Shi
authors.forename: Gatien
authors.initials: G
authors.lastname: Moriceau
authors.forename: Xiangju
authors.initials: X
authors.lastname: Kong
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.forename: Ramin
authors.initials: R
authors.lastname: Nazarian
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.forename: Antonella
authors.initials: A
authors.lastname: Bacchiocchi
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Dahlman
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005091:Exons; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010091:Oximes / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C561627:dabrafenib