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Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance.

Authors
  • H, Shi
  • G, Moriceau
  • X, Kong
  • Mk, Lee
  • Hane Lee
  • Rc, Koya
  • C, Ng
  • T, Chodon
  • Ra, Scolyer
  • Kb, Dahlman
  • Ja, Sosman
  • Rf, Kefford
  • Gv, Long
  • Stanley F. Nelson
  • A, Ribas
  • Rs, Lo
Type
Published Article
Journal
Nature Communications
Publisher
Springer Nature
Volume
3
Pages
724–724
Identifiers
DOI: 10.1038/ncomms1727
Source
Nelson Lab
License
Unknown

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.

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