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.
Original language | English |
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Article number | 1727 |
Pages (from-to) | 1-8 |
Number of pages | 8 |
Journal | Nature Communications |
Volume | 3 |
DOIs | |
Publication status | Published - 2012 |
Externally published | Yes |