Abstract 2156: Preclinical combinations of vemurafenib, a selective BRAF inhibitor, with other targeted therapies in BRAFV600E colorectal cancer models

Abstract

Abstract Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8% of all human (solid) tumors, including about 10% of colorectal cancers (CRCs). Vemurafenib (RG7204, PLX4032) is a first-in-class, BRAF-specific small molecule inhibitor that dose-dependently inhibits tumor growth in BRAFV600E CRC xenografts. Despite these encouraging preclinical findings, unlike the remarkable responses observed in melanoma, single agent vemurafenib in a Phase I extension trial of 21 patients with previously treated metastatic CRC resulted in a modest 5% response rate. We therefore explored a range of combinations of vemurafenib with different novel targeted therapies including a MEK inhibitor, an AKT inhibitor, a PI3K inhibitor, an mTOR/PI3K dual inhibitor and an EGFR inhibitor in BRAFV600E CRC cell lines. The consequences of these combinations on proliferation were analyzed by MTT assay and the combined effect was determined by combination index (CI) calculated using CalcuSyn software. Western analysis and Annexin V staining were utilized to evaluate combination effects on downstream signaling events and apoptosis induction. Optimized doses of both vemurafenib and a MEK inhibitor were tested as single agents and in combination in CRC xenograft models in nude mice. Synergistic anti-proliferative effects were observed with combinations of vemurafenib and other targeted therapies in the BRAFV600E positive CRC cell lines tested. More effective signaling inhibition and apoptosis induction were observed with the combinations than either agent alone. Combining vemurafenib with a MEKi delivered greater anti-tumor activity and increased life span of animals in the LS411N CRC xenograft model. In a BRAF-mutant CRC xenograft model with inherent resistance to vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced by combining with an AKT inhibitor. These in vitro and in vivo data suggest that the administration of vemurafenib in combination with novel targeted therapies may be effective in delivering enhanced and sustained clinical antitumor efficacy in colorectal cancers harboring the BRAFV600E mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2156. doi:1538-7445.AM2012-2156