Response to BRAF-targeted Therapy Is Enhanced by Cotargeting VEGFRs or WNT/b-Catenin Signaling in BRAF-mutant Colorectal Cancer Models

Abstract

The fact that 10% of colorectal cancer tumors harbor BRAF cell lines in vitro. The selective and potent VEGFR inhibitor axitinib V600E mutations suggested targeting BRAF as a potential therapy. was most effective against BRAF-mutant colorectal cancer cell lines However, BRAF inhibitors have only limited single-agent efficacy in in vitro, but the addition of vemurafenib did not significantly this context. The potential for combination therapy has been shown increase these effects. When tested in vivo in animal tumor models, by the BEACON trial where targeting the EGF receptor with both pyrvinium and axitinib were able to significantly increase the cetuximab greatly increased efficacy of BRAF inhibitors in ability of vemurafenib to attenuate tumor growth in xenografts of BRAF-mutant colorectal cancer. Therefore, we explored whether BRAF-mutant colorectal cancer cells. The magnitude of these effects efficacy of the mutant BRAF inhibitor vemurafenib could be was comparable with that induced by a combination of vemurafenib enhanced by cotargeting of either oncogenic WNT/b-catenin sig- and cetuximab. This was associated with additive effects on release naling or VEGFR signaling. We find the WNT/b-catenin inhibitors from tumor cells and tumor microenvironment cell types of sub-pyrvinium, ICG-001 and PKF118-310 attenuate growth of colostances that would normally aid tumor progression. Taken together, rectal cancer cell lines in vitro with BRAF-mutant lines being these preclinical data indicate that the efficacy of BRAF inhibitor relatively more sensitive. Pyrvinium combined with vemurafenib therapy in colorectal cancer could be increased by cotargeting either additively or synergistically attenuated growth of colorectal cancer WNT/b-catenin or VEGFRs with small-molecule inhibitors.