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

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, Georgina V. Long, Stanley F. Nelson, Antoni Ribas and Roger S. Lo ()
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Hubing Shi: University of California, Los Angeles
Gatien Moriceau: University of California, Los Angeles
Xiangju Kong: University of California, Los Angeles
Mi-Kyung Lee: University of California, Los Angeles
Hane Lee: David Geffen School of Medicine, University of California, Los Angeles
Richard C. Koya: David Geffen School of Medicine, University of California, Los Angeles
Charles Ng: David Geffen School of Medicine, University of California, Los Angeles
Thinle Chodon: David Geffen School of Medicine, University of California, Los Angeles
Richard A. Scolyer: Melanoma Institute of Australia
Kimberly B. Dahlman: Department of Cancer Biology
Jeffrey A. Sosman: Vanderbilt-Ingram Cancer Center
Richard F. Kefford: Melanoma Institute of Australia
Georgina V. Long: Melanoma Institute of Australia
Stanley F. Nelson: David Geffen School of Medicine, University of California, Los Angeles
Antoni Ribas: David Geffen School of Medicine, University of California, Los Angeles
Roger S. Lo: University of California, Los Angeles

Nature Communications, 2012, vol. 3, issue 1, 1-8

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms1727

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