Vemurafenib (PLX4032, Zelboraf®), a BRAF Inhibitor, Modulates ABCB1-, ABCG2-, and ABCC10-Mediated Multidrug Resistance

 In this study, we examined the in vitro effects of vemurafenib, a specific inhibitor of V600E mutated BRAFenzyme, on the response of cells overexpressing the ATP binding cassette (ABC) efflux transporters ABCG2, ABCB1, ABCC1 and ABCC10. Vemurafenib, at 5 µM and 20 µM, produced a significant concentration-dependent increase in the cytotoxicity of paclitaxel in cells overexpressing ABCB1 and ABCC10 and mitoxantrone in cells overexpressing ABCG2. Vemurafenib also significantly enhanced the accumulation of paclitaxel in cell lines overexpressing ABCB1 and ABCC10. Vemurafenib significantly increased the intracellular accumulation of mitoxantrone in cells overexpressing ABCG2. In contrast, vemurafenib did not significantly alter the sensitivity of ABCC1 overexpressing HEK/ABCC1 cells to vincristine. Finally, as determined by Western blotting, vemurafenib (20 µM) did not significantly alter the expression of the proteins for ABCG2, ABCC10 or ABCB1. Thus, vemurafenib most likely reverses multidrug resistance by altering the transport function of these aforementioned ABC transporters, as opposed to affecting the expression of ABC proteins. The docking analysis of vemurafenib with the ABCB1 homology model also suggested that vemurafenib binds to the ABCB1 and ABCG2 drug binding site. These findings suggest that combination of specific inhibitors like vemurafenib with chemotherapeutic drugs may be used to overcome multidrug resistance in cells that overexpress ABCB1, ABCC10 and/or ABCG2 transporters.