The Bcl-2 family protein inhibitor, ABT-263, broadly potentiates the cytotoxicity of other therapeutic agents in vitro

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The interplay between pro-survival (Bcl-2, Bcl-xL, Bcl-w, Mcl-1, A-1) and pro-apoptotic (Bad, Bim, Bid, Noxa, Bak, Bax, etc.) Bcl-2 family proteins centrally regulate the intrinsic apoptotic pathway. Expression of the pro-survival family members is a common mechanism by which tumor cells evade apoptosis in the face of cellular stresses that would kill normal cells. Bcl-2 and Bcl-X_L, for example, exert their protective effects by directly binding to and sequestering their proapoptotic counterparts. ABT-263 is an orally bioavailable small molecule antagonist of pro-survival Bcl-2 family proteins with a K_i of < 1 nM against Bcl-2, Bcl-X_L, and Bcl-w. In an extensive screen of human tumor cell lines, this agent exhibited potent single agent cytotoxicity against a subset of tumor types that includes small cell lung carcinomas and B-cell and T-cell derived malignancies. However, based on the current mechanistic understanding of the Bcl-2 family, antagonism of the pro-survival members should more generally potentiate the effects of exogenous pro-apoptotic stimuli. To evaluate the ability of ABT-263 to potentiate the effects of chemotherapy in solid tumors, we examined its activity in combination with 30 different therapeutic agents across 40 human tumor cell lines representing 12 major solid tumor types. ABT-263 displayed broad synergistic activity with numerous therapeutic agents across multiple solid tumor types. This illustrates the potential utility of ABT-263 in a wider clinical setting when used in combination with other therapies. Underlying mechanisms involved in the observed combination synergies will be discussed.