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Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance

Author

Listed:
  • Hubing Shi

    (University of California, Los Angeles
    David Geffen School of Medicine, University of California, Los Angeles)

  • Gatien Moriceau

    (University of California, Los Angeles
    David Geffen School of Medicine, University of California, Los Angeles)

  • Xiangju Kong

    (University of California, Los Angeles
    David Geffen School of Medicine, University of California, Los Angeles)

  • Mi-Kyung Lee

    (University of California, Los Angeles
    David Geffen School of Medicine, University of California, Los Angeles)

  • Hane Lee

    (David Geffen School of Medicine, University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Richard C. Koya

    (David Geffen School of Medicine, University of California, Los Angeles
    University of California, Los Angeles)

  • Charles Ng

    (David Geffen School of Medicine, University of California, Los Angeles
    University of California)

  • Thinle Chodon

    (David Geffen School of Medicine, University of California, Los Angeles
    University of California)

  • Richard A. Scolyer

    (Melanoma Institute of Australia
    Royal Prince Alfred Hospital, University of Sydney
    University of Sydney)

  • Kimberly B. Dahlman

    (Department of Cancer Biology
    Vanderbilt-Ingram Cancer Center)

  • Jeffrey A. Sosman

    (Vanderbilt-Ingram Cancer Center
    Department of Medicine)

  • Richard F. Kefford

    (Melanoma Institute of Australia
    University of Sydney
    Westmead Millenium Institute, University of Sydney)

  • Georgina V. Long

    (Melanoma Institute of Australia
    University of Sydney
    Westmead Millenium Institute, University of Sydney)

  • Stanley F. Nelson

    (David Geffen School of Medicine, University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles
    Jonsson Comprehensive Cancer Center, University of California, Los Angeles)

  • Antoni Ribas

    (David Geffen School of Medicine, University of California, Los Angeles
    University of California, Los Angeles
    University of California
    Jonsson Comprehensive Cancer Center, University of California, Los Angeles)

  • Roger S. Lo

    (University of California, Los Angeles
    David Geffen School of Medicine, University of California, Los Angeles
    Jonsson Comprehensive Cancer Center, University of California, Los Angeles
    University of California, Los Angeles)

Abstract

The development of acquired drug resistance hampers the long-term success of B-RAF inhibitor therapy for melanoma patients. Here we show V600EB-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, V600EB-RAF overexpression and knockdown conferred B-RAF inhibitor resistance and sensitivity, respectively. In V600EB-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 V600EB-RAF bypass, which is sensitive to C-RAF knockdown, V600EB-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.

Suggested Citation

  • Hubing Shi & Gatien Moriceau & Xiangju Kong & Mi-Kyung Lee & Hane Lee & Richard C. Koya & Charles Ng & Thinle Chodon & Richard A. Scolyer & Kimberly B. Dahlman & Jeffrey A. Sosman & Richard F. Kefford, 2012. "Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance," Nature Communications, Nature, vol. 3(1), pages 1-8, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1727
    DOI: 10.1038/ncomms1727
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