Melanoma whole-exome sequencing identifiesV600EB-RAF amplification-mediated acquiredB-RAF inhibitor resistance

摘要

The development of acquired drug resistance hampers the long-term success of B-RAF inhibitortherapy for melanoma patients. Here we showV600EB-RAF copy-number gain as a mechanismof acquired B-RAF inhibitor resistance in 4 out of 20 (20%) patients treated with B-RAFinhibitor. In cell lines, V600EB-RAF overexpression and knockdown conferred B-RAF inhibitorresistance and sensitivity, respectively. InV600EB-RAF amplification-driven (versus mutantN-RAS-driven) B-RAF inhibitor resistance, extracellular signal-regulated kinase reactivationis saturable, with higher doses of vemurafenib down-regulating phosho-extracellular signalregulated kinase and re-sensitizing melanoma cells to B-RAF inhibitor. These two mechanismsof extracellular signal-regulated kinase reactivation are sensitive to the mEK1/2 inhibitorAZD6244/selumetinib or its combination with the B-RAF inhibitor vemurafenib. In contrastto 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 signalregulated kinase reactivation underlying acquired B-RAF inhibitor resistance in melanoma.