Data from Synergistic Combination of Novel Tubulin Inhibitor ABI-274 and Vemurafenib Overcomes Vemurafenib Acquired Resistance in BRAFV600E Melanoma
Year: 2023
Type: other
Abstract: Acquired clinical resistance to vemurafenib, a selective BRAFV600E inhibitor, arises frequently after short-term chemotherapy. Because inhibitions of targets in the RAF–MEK–ERK pathway result in G0–G1 cell-cycle arrest, vemurafenib-resistant cancer cells are expected to escape this cell-cycle arrest and progress to the subsequent G2–M phase. We hypothesized that a combined therapy using vemurafenib with a G2–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 an A375RF21 subline with significant acquired resistance to vemurafenib and confirmed the strong synergistic effect. Next, we studied the potential mechanisms of overcoming vemurafenib resistance. Flow cytometry confirmed that the combination of ABI-274 and vemurafenib synergistically arrested cells in the G1–G2–M phase, and significantly increased apoptosis in both parental A375 and the vemurafenib-resistant A375RF21 cells. Western blot analysis revealed that the combination treatment effectively reduced the level of phosphorylated and total AKT, activated the apoptosis cascade, and increased cleaved caspase-3 and cleaved PARP, but had no significant influence on the level of extracellular signal–regulated kinase (ERK) phosphorylation. Finally, in vivo coadministration 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 patients with melanoma who inevitably become resistant to current vemurafenib therapy. Mol Cancer Ther; 13(1); 16–26. ©2013 AACR.
Authors: Jin Wang, Jianjun Chen, Duane D. Miller, Wei Li
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4362494955