Abstract 723: Acquired resistance to PLX4720 involves both ERK re-activation and suppression of BH3-only proteins in human melanoma cells

Abstract

Abstract B-RAF is mutated to a constitutively active form in 8% of human cancers. Tumors harboring mutant B-RAF are often dependent on B-RAF-MEK-ERK1/2 signaling for the maintenance of malignant properties. Evidence for oncogene addiction has been underscored in early phase clinical trials in which the RAF inhibitor, PLX4032/RG7204, caused partial or complete responses in 81% of mutant B-RAF harboring melanoma patients. However, the average duration of response was 7-8 months with the majority of patients relapsing, indicating the acquisition of resistance to PLX4032. Since understanding the mechanisms of resistance will drive the design of future combinatorial trials, we undertook an in vitro analysis of melanoma cell acquired resistance to PLX4720, the tool compound for PLX4032. Through continuous culture in the presence of PLX4720, we developed mutant B-RAF melanoma cell populations that display resistance to B-RAF inhibitors. Resistance was associated with a partial re-activation of ERK1/2 signaling, recovery of G1/S cell cycle events, and suppression of BH3-only proteins, Bim-EL and Bmf, in the presence of PLX4720. Preventing the ERK1/2 re-activation with MEK inhibitors blocked G1-S cell cycle events but failed to induce apoptosis or up-regulate Bim-EL and Bmf levels. These data indicate that acquired resistance to PLX4032/4720 likely involves ERK1/2 pathway re-activation and ERK1/2-independent silencing of BH3-only protein up-regulation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 723. doi:10.1158/1538-7445.AM2011-723