Abstract B19: Discovery of novel tubulin inhibitor ABI-274 whose synergistic combination with vemurafenib overcome acquired vemurafenib resistance in BRAF mutated melanoma

Abstract

Abstract Acquired clinical resistance to BRAF inhibitors such as vemurafenib or dabrafefnib arises frequently after short term of these targeted therapy. We hypothesized that a combined therapy using vemurafenib with a G2/M phase blocking agent will arrest resistant cells and overcome vemurafenib resistance. To test this hypothesis, we performed combination studies using our recently discovered tubulin inhibitor ABI-274 and vemurafenib on both vemurafenib-sensitive cells and a resistant A375RF21 sub line. The combination showed strong synergy in vitro, synergistically arrested cells in G1/G2/M phase, and significantly enhanced cancer cell apoptosis. In vivo co-administration of vemurafenib with ABI-274 showed strong synergistic efficacy in the vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in melanoma patients who inevitably become resistant to current vemurafenib therapy. This work was supported by NIH grants R01CA148706, 1S10OD010678-01 and 1S10RR026377-01. Citation Format: Jin Wang, Jianjun Chen, Duane D. Miller, Wei Li. Discovery of novel tubulin inhibitor ABI-274 whose synergistic combination with vemurafenib overcome acquired vemurafenib resistance in BRAF mutated melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B19.