Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer
Menée sur des lignées cellulaires de cancer colorectal présentant la mutation V600E du gène BRAF et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale du vemurafenib
The protein kinase BRAF is a key component of the RAS-RAF signaling pathway which plays an important role in regulating cell proliferation, differentiation, and survival. Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8% of all human (solid) tumors, including colorectal cancers (CRCs). Here, we report the preclinical characterization of vemurafenib (RG7204; PLX4032; RO5185426), a first-in-class, specific small molecule inhibitor of BRAFV600E in BRAF-mutated CRC cell lines and tumor xenograft models. As a single agent, vemurafenib showed dose-dependent inhibition of ERK and MEK phosphorylation, thereby arresting cell proliferation in BRAFV600E expressing cell lines and inhibiting tumor growth in BRAFV600E bearing xenograft models. Because vemurafenib has demonstrated limited single-agent clinical activity in BRAFV600E-mutant metastatic CRC, we therefore explored a range of combination therapies with both standard agents and targeted inhibitors in preclinical xenograft models. In a BRAF-mutant CRC xenograft model with de novo resistance to vemurafenib (RKO), tumor growth inhibition by vemurafenib was potentiated by combining with an AKT inhibitor (MK-2206). The addition of vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or irinotecan, or erlotinib resulted in increased antitumor activity and improved survival in xenograft models. Together, our findings suggest that the administration of vemurafenib in combination with standard-of-care or novel targeted therapies may lead to enhanced and sustained clinical antitumor efficacy in colorectal cancers harboring the BRAFV600E mutation.
Cancer Research 2011