Reference Detail

Ref Type

Journal Article

PMID

(36198029)

Authors

Tran KB, Kolekar S, Wang Q, Shih JH, Buchanan CM, Deva S, Shepherd PR

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	21	12	2022 Dec 02	1777-1787	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	colorectal cancer	sensitive	Pyrvinium + Vemurafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, combination treatment with Zelboraf (vemurafenib) and Pyrvinium resulted in decreased viability in colorectal cancer cell lines harboring BRAF V600E in culture, and led to synergistic inhibition of tumor growth in a cell line xenograft model (PMID: 36198029).	36198029
BRAF V600E	colorectal cancer	sensitive	Axitinib + Vemurafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, combination treatment with Zelboraf (vemurafenib) and Inlyta (axitinib) resulted in decreased cell viability in colorectal cancer cell lines harboring BRAF V600E in culture, and led to synergistic inhibition of tumor growth in cell line xenograft models (PMID: 36198029).	36198029