Melanoma whole exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance
By Hubing Shi, G. Moriceau, X. Kong, Mi-Kyung Lee, Hane Lee, R. Koya, Charles Ng, T. Chodon, R. Scolyer, K. Dahlman and 6 more. Nature Communications, 2012
643 citations recorded by the source corpus.
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. B-RAF is mutated in a large proportion of melanomas, and the first small molecule inhibitor has recently been approved for melanoma treatment. Here, by exome sequencing melanoma samples, Shi and colleagues show that B-RAF is amplified in tumours that have acquired resistance to the B-RAF inhibitor vemurafenib.
Subfields: Computational Theory and Mathematics, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/8a35ec0a8298830fe51045f838cb71173dfb5d38
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Citations in the corpus
- Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. (2013, background): “BRAF amplification, as well as expression of drug resistant BRAF splice-variants lacking N-terminal regulatory regions, have been described as clinical resistance mechanisms in PLX4032-relapsed melanoma patients while MEK1 was identified in a patient who relapsed on treatment with the MEK inhibitor ”
- Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain (2013, background): “Consistent with our results, previous reports have shown that BRAFV600E amplification leads to vemurafenib resistance (Shi et al., 2012).”
- Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. (2014, neutral): “Hypertension 46 (22) 8 (4) 29 (14) 10 (5)”