LAUSR

BCL2 and MCL1 are commonly expressed pro-survival (anti-apoptotic) proteins in hematological cancers and play important roles in their biology either through dysregulation or by virtue of intrinsic importance to the cell-of-origin of the malignancy. A new class of small molecule anti-cancer drugs, BH3-mimetics, now enable specific targeting of these proteins in patients. BH3-mimetics act by inhibiting the pro-survival BCL2 proteins to enable the activation of BAX and BAK, apoptosis effectors which permeabilize the outer mitochondrial membrane, triggering apoptosis directly in many cells and sensitizing others to cell death when combined with other anti-neoplastic drugs. Venetoclax, a specific inhibitor of BCL2, is the first approved in class, demonstrating striking single agent activity in chronic lymphocytic leukemia (CLL) and in other lymphoid neoplasms, as well as activity against acute myeloid leukemia (AML), especially when used in combination. Key insights from the venetoclax experience include that responses occur rapidly, with major activity as monotherapy proving to be the best indicator for success in combination regimens. This emphasizes the importance of adequate single agent studies for drugs in this class. Furthermore, secondary resistance is common with long-term exposure and often mediated by genetic or adaptive changes in the apoptotic pathway, suggesting that BH3-mimetics are better suited to limited-duration, rather than continuous, therapy. The success of venetoclax has inspired development of BH3-mimetics targeting MCL1. Despite promising preclinical activity against MYC-driven lymphomas, myeloma and AML, their success may particularly depend on their tolerability profile given physiological roles for MCL1 in several non-hematological tissues.