Restoring the switch for cancer cell death: Targeting the apoptosis signaling pathway

Purpose. The relevance of apoptosis to cancer development and pharmacologic agents that target this pathway in selected malignancies are described. Summary. Apoptosis is a tightly regulated biological process mediated by both proapoptotic (i.e., prodeath) and antiapoptotic (i.e., prosurvival) proteins. While apoptosis represents a well-established effector mechanism induced by conventional chemotherapy in many malignancies, the development of apoptosis-based targeted therapy is relatively new. The pharmacologic restoration of apoptotic functions, either by blocking the action of antiapoptotic proteins/regulators (e.g., through investigational therapies such as inhibitors of apoptosis proteins, SMAC [second mitochondriaderived activator of caspases] mimetics, MDM2 [murine double minute 2] antagonists) or by inducing apoptosis (e.g., through investigational agonistic monoclonal antibodies or fusion proteins), holds robust potential for cancer pharmacotherapy. Notably, BH domain 3 (BH3) mimetics, a new class of small molecules that block the action antiapoptotic proteins, are touted a success for apoptosis-based targeted therapy. Venetoclax, a synthetic peptide that belongs to this class of BH3 mimetics, is currently approved by the Food and Drug Administration for the treatment of relapsed/refractory chronic lymphocytic leukemia in patients with 17p deletion as a single agent. This agent has been increasingly used either alone or as part of combination therapy for diverse hematologic malignancies in clinical trials. Conclusion. Advances in the understanding of molecular mechanisms of apoptosis have given rise to more-refined targeted therapies for diverse malignancies, with the goal to improve survival outcome while sparing treatment-related toxicities.