Response to BRAF targeted therapy is enhanced by co-targeting VEGFRs or WNT/β-Catenin signaling in BRAF-mutant colorectal cancer models.

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