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

Abstract

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

• Authors: Khanh B Tran, Sharada Kolekar, Qian Wang, Jen-Hsing Shih, Christina M Buchanan, Sanjeev Deva, Peter R Shepherd
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 21 Issue 12 Pg. 1777-1787 (12 02 2022) ISSN: 1538-8514 [Electronic] United States
• PMID: 36198029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Vemurafenib
• Proto-Oncogene Proteins B-raf
• Cetuximab
• beta Catenin
• Axitinib
• Protein Kinase Inhibitors
• BRAF protein, human

Topics

• Animals
• Humans
• Vemurafenib (pharmacology)
• Proto-Oncogene Proteins B-raf
• Cetuximab (pharmacology, therapeutic use)
• beta Catenin (genetics, metabolism)
• Axitinib (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• Cell Line, Tumor
• Mutation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Wnt Signaling Pathway
• Tumor Microenvironment