Synergistic combination of novel tubulin inhibitor ABI-274 and vemurafenib overcome vemurafenib acquired resistance in BRAFV600E melanoma.

ABSTRACT: Acquired clinical resistance to vemurafenib, a selective BRAF(V600E) inhibitor, arises frequently after short-term chemotherapy. Because inhibitions of targets in the RAF-MEK-ERK pathway result in G(0)-G(1) cell-cycle arrest, vemurafenib-resistant cancer cells are expected to escape this cell-cycle arrest and progress to the 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 of our novel tubulin inhibitor ABI-274 and vemurafenib on parental human A375 and MDA-MB-435 melanoma cell lines to be 0.32 and 0.1, respectively, suggesting strong synergy for the combination. We then developed a

SUBMITTER: Wang J 

PROVIDER: S-EPMC3947172 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature