Beyond BCL-2 Inhibition in Acute Myloid Leukemia: Other Approaches to Leverage the Apoptotic Pathway.

BCL-2 inhibition has transformed the therapeutic landscape of acute myeloid leukemia (AML) but is not curative for the majority of patients. Consequently, there has been growing interest in targeting other facets of the apoptotic machinery to improve outcomes. These approaches include targeting the intrinsic and extrinsic apoptotic pathway, inducing apoptosis via p53 activation, and others. Targeting the intrinsic apoptotic pathway includes MCL-1 antagonism and BCL-xL inhibition. MCL-1 can be targeted via direct inhibitors as well as via indirect mechanisms to downregulate MCL-1 including inhibition of cyclin dependent kinases and Nedd8 activating enzyme. The extrinsic apoptotic pathway could be harnessed via inhibition of inhibitor of apoptosis proteins, agonism of the TNF-related apoptosis-inducing ligand receptors and inhibiting FLICE-like inhibitor protein. Approaches inducing p53-mediated apoptosis are being evaluated using inhibitors of MDM2, dual inhibitor of MDM2/X in TP53 wild-type AML and p53 reactivators in TP53-mutant myeloid disorders. Several such agents are in early clinical development and rationale combinations of these agents may help improving outcomes for patients with AML.