Abstract 1724: BRAF inhibition is enhanced by BH3-mimetic through BIM induction.

Abstract

Abstract Vemurafenib (Vem) is a highly selective inhibitor of mutant BRAF, FDA-approved for the treatment of patients with BRAF-positive advanced melanoma. While response rates to Vem are high, the emergence of resistance is common, placing high priority in the development of strategies to enhance Vem efficiency. Navitoclax is a BH3-mimetic that binds and inactivates the anti-apoptotic proteins BCL-2, BCL-xl, and BCL-w and leads to apoptosis in tumors with low expression of another anti-apoptotic protein, MCL-1. Our data demonstrates that treatment of BRAF-mutant melanoma patients with Vem is associated with decreased expression of MCL-1 in addition to an increase in the pro-apoptotic, BH3-only protein BIM in serial biopsy samples. Therefore, we hypothesize that the combination of PLX-4720 (Vem analog) with navitoclax will result in increased anti-tumor activity. To test our hypothesis, we performed cell viability studies, Annexin:PI and ELISA apoptosis assays in addition to protein and mRNA analysis. In-vivo studies were performed in two BRAF mutant xenograft models using navitoclax and PLX-4720. In-vitro, our cell viability studies demonstrated that concurrent treatment with PLX-4720 and navitoclax results in an additive viability reduction in BRAF mutant but not in BRAF WT cell lines. The decrease in cell viability correlated to downmodulation of MCL-1 and BIM induction after PLX-4720 treatment, with further enhancement of BIM expression and PARP cleavage after adding navitoclax. In vivo, the navitoclax enhanced the efficacy of PLX-4720 in both xenograft models. The combination of a selective BRAF inhibitor with a BH3-mimetic may be a promising therapeutic strategy to enhance the clinical efficacy of BRAF inhibitors. Citation Format: Dennie T. Frederick, Roberto A. Salas Fragomeni, Taylor Hoff, Zachary A. Cooper, James W. Mier, Jennifer A. Wargo, Ryan J. Sullivan. BRAF inhibition is enhanced by BH3-mimetic through BIM induction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1724. doi:10.1158/1538-7445.AM2013-1724