Overcoming Acquired Resistance in BRAFV600 Melanoma Using a Combination of ABI-274 and Vemurafenib in a Predictive A375RF21Model

摘要

Acquired clinical resistance to vemurafenib, a selective BRAF[V600E] inhibitor, arises frequently after short term chemotherapy. Since inhibitions of targets in theRAF-MEK-ERK pathway result in G[0]/G[1] cell cycle arrest, vemurafenib-resistant cancer cellsare expected to escape thiscell cycle arrest and progress to subsequent G[2]/M phase. We hypothesized that a combined therapy using vemurafenib with a G[2]/M phase blocking agent will trap resistant cells and overcome vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values ofour novel tubulin inhibitor ABI-274 and vemurafenib on parental human A375 and MDA-MB-435 human melanoma cell lines to be 0.32 and 0.1, respectively, suggesting strong synergistic combination.