Mitochondrial apoptosis and BH3 mimetics

Abstract

The BCL2-selective BH3 mimetic venetoclax was recently approved for the treatment of relapsed, chromosome 17p-deleted chronic lymphocytic leukemia (CLL) and is undergoing extensive testing, alone and in combination, in lymphomas, acute leukemias, and solid tumors. Here we summarize recent advances in understanding of the biology of BCL2 family members that shed light on the action of BH3 mimetics, review preclinical and clinical studies leading to the regulatory approval of venetoclax, and discuss future investigation of this new class of antineoplastic agent.

Keywords: BAK activation; BAX activation; BCL-2 inhibitors; BH3 mimetics; venetoclax.

Figure 1.. Two models of BH3 mimetic action.

In Model 1 (left), BH3 mimetics are thought to displace activated BIM from anti-apoptotic BCL2 family members, allowing BIM to subsequently activate BAX and BAK . In Model 2 (right), BAK and/or BAX are constitutively activated and are displaced from anti-apoptotic BCL2 family members by BH3 mimetics . Model 2 is more compatible with recent studies showing that BAK and BAX can be activated in the absence of BH3-only proteins under cell-free conditions and in gene-targeted HCT116 cells . It is, however, possible that one mode of activation predominates in some cell lines or tissues and the other mode predominates in others. Table below figure, summary of BCL2 subfamilies, their functions, and members.