Antitumorigenic effect of combination treatment with BRAF inhibitor and cisplatin in colorectal cancer in vitro and in vivo

Abstract

Abstract Purpose In colorectal cancer (CRC), BRAF inhibitor (BRAFi) monotherapy appears ineffective, while cisplatin treatment is associated with adverse effects, drug resistance and reduced efficacy. Herein, we seek to explore a combinatorial approach to increase the likelihood of effectively killing colorectal cancer cells. Methods We examined the combined effect of BRAFi (PLX4720, Vemurafenib, Dabrafenib, Encorafenib) and cisplatin treatment in BRAFV600E-mutated (RKO, HT29, Colo-205) and BRAFwt (Caco-2) cell lines, as well as in mouse xenografts of RKO cells. Results Following cisplatin-only treatment, all cell lines showed accumulation within subG1 (apoptotic cells) and G2/M phases, as well as phosphorylation of ERK1/2 and H2AX. Following BRAFi-only treatment, BRAFV600E-mutated cells showed accumulation within G0/G1 phase, reduced distribution in the S and G2/M phases, inhibition of ERK1/2 phosphorylation and increased phosphorylation of H2AX. BRAFi had no effect on BRAFwt Caco-2 cell line. Combined BRAFi and cisplatin treatment synergistically decreased RKO cells viability, reduced phosphorylation of ERK1/2 and increased phosphorylation of H2AX. Importantly, in mouse xenografts of RKO cells, combined PLX4720 and cisplatin treatment showed superior therapeutic potential than each monotherapy (P < 0.001). Conclusion In in vitro and in vivo preclinical models, BRAFi and cisplatin combined treatment has shown an improved antitumor effect, rendering it a potential anticancer treatment strategy for BRAF-mutant colon cancer patients.