Abstract A28: Apoptosis induction with the MEK inhibitor AZD6244 and BH3 mimetic ABT-737 in melanoma.

Over sixty percent of patients with melanoma have the activating B-RAF V600E mutation leading to increased activation of the mitogen activated protein kinase (MAPK) pathway. The downstream effects of MAPK pathway activation are increased proliferation, invasiveness, and survival through the regulation of down-stream targets such as the pro-apoptotic protein BIM. Prior studies have shown that inhibiting MAPK kinase (MEK), downstream of constitutively active B-RAF, can up-regulate BIM, leading to increased apoptosis in melanoma cell lines. However, single agent MEK inhibition has had limited effectiveness in the clinical setting for late-stage melanoma patients, likely due to an inadequate induction of apoptosis. We hypothesized that combining the clinically relevant MEK inhibitor, AZD6244 (ARRY142886) with a BCL-2 inhibitor, ABT-737, would lead to increased apoptosis over single agent therapies in melanoma cells via BIM activation and pan-BCL-2 inhibition. We compared single treatments of AZD6244 and ABT737 to the combination of these agents in a panel of melanoma tumor cell lines chosen by mutational status in both a monolayer system and an anchorage independent system. The combination of AZD6244 and ABT-737 had a synergistic effect on decreasing cell viability and increasing apoptosis compared to single agent treatments regardless of B-RAF mutational status. Western blotting revealed dramatic increases in cleaved caspase 3 and PARP with combinational treatment compared to single agent therapy. These early pre-clinical experiments indicate that AZD6244 combined with ABT-737 may be an effective combination therapy for patients with late-stage melanoma. Currently, we have plans to conduct in vivo studies to translate these results into the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A28.