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Inhibition of BRAF improves therapeutic efficacy of BRAF-mutant melanoma. However, drug resistance to BRAF inhibitor is inevitable, and the drug resistance mechanisms still remain to be elucidated. Here, BRAF mutant cells A375 and SK-MEL-28 were chosen and treated with BRAF inhibitor vemurafenib, and the results showed that the ERK signaling pathway was blocked in these cells. Then, vemurafenib-resistant cells were constructed, and we found that drug resistance-related gene P-gp was overexpressed in the two cell lines. In addition, the histone acetylation was significantly increased on the P-gp promoter region, which suggested that the epigenetic modification participated in the P-gp overexpression. Furthermore, JQ1, a bromodomain inhibitor, was added to the vemurafenib-resistant cells and sensitizes the vemurafenib-induced melanoma cell apoptosis. In C57BL/6 mice intravenously injected with vemurafenib-resistant melanoma cells, cotreatment of vemurafenib and JQ1 also severely suppressed melanoma lung metastasis. Taken together, our findings may have important implications for the combined use of vemurafenib and JQ1 in the therapy for melanoma treatment.

The BET-bromodomain inhibitor JQ1 mitigates vemurafenib drug resistance in melanoma