Journal
NATURE COMMUNICATIONS
Volume 3, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms1727
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Categories
Funding
- National Cancer Institute [K22CA151638, K24CA097588]
- V Foundation for Cancer Research
- Melanoma Research Foundation
- Melanoma Research Alliance
- American Skin Association
- Joint Center for Translational Medicine
- Sidney Kimmel Foundation
- Stand Up to Cancer
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Wesley Coyle Memorial Fund
- Ian Copeland Melanoma Fund
- Ruby Family Foundation
- Louis Belley and Richard Schnarr Fund
- Seaver Institute
- National Health and Medical Research Council of Australia [402761]
- Cancer Institute New South Wales (CINSW) [05/TPG/1-01]
- American Cancer Society
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The development of acquired drug resistance hampers the long-term success of B-RAF inhibitor therapy for melanoma patients. Here we show B-V600E-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, B-V600E-RAF overexpression and knockdown conferred B-RAF inhibitor resistance and sensitivity, respectively. In B-V600E-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 B-V600E-RAF bypass, which is sensitive to C-RAF knockdown, B-V600E-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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