title: Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance.
abstract: The development of acquired drug resistance hampers the long-term success of B-RAF inhibitor therapy for melanoma patients. Here we show (V600E)B-RAF copy-number gain as a mechanism of acquired B-RAF inhibitor resistance in 4 out of 20 (20%) patients treated with B-RAF inhibitor. In cell lines, (V600E)B-RAF overexpression and knockdown conferred B-RAF inhibitor resistance and sensitivity, respectively. In (V600E)B-RAF amplification-driven (versus mutant N-RAS-driven) B-RAF inhibitor resistance, extracellular signal-regulated kinase reactivation is saturable, with higher doses of vemurafenib down-regulating phosho-extracellular signal-regulated kinase and re-sensitizing melanoma cells to B-RAF inhibitor. These two mechanisms of extracellular signal-regulated kinase reactivation are sensitive to the MEK1/2 inhibitor AZD6244/selumetinib or its combination with the B-RAF inhibitor vemurafenib. In contrast to mutant N-RAS-mediated (V600E)B-RAF bypass, which is sensitive to C-RAF knockdown, (V600E)B-RAF amplification-mediated resistance functions largely independently of C-RAF. Thus, alternative clinical strategies may potentially overcome distinct modes of extracellular signal-regulated kinase reactivation underlying acquired B-RAF inhibitor resistance in melanoma.
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, 52-121 CHS, 10833 Le Conte Avenue, 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: Mi-Kyung
authors.initials: MK
authors.lastname: Lee
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.forename: Charles
authors.initials: C
authors.lastname: Ng
authors.forename: Thinle
authors.initials: T
authors.lastname: Chodon
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Dahlman
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
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 / Q000494:pharmacology; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059472:Exome; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1