Apoptosis is a metazoan process of controlled cell elimination that plays critical roles in embryonic development and adult tissue homeostasis. Apoptosis dysregulation contributes to several important diseases, including cancer. Two distinct yet interconnected signaling pathways control apoptosis by activating a core intracellular machinery of death proteases called caspases. The intrinsic apoptotic pathway engages caspases via members of the BCL-2 protein family and the mitochondria in reaction to severe cellular damage or stress. The extrinsic pathway activates caspases via cell-surface death receptors, which respond to cognate death ligands expressed on immune-effector cells. Tumor cells can acquire various apoptosis-evasion mechanisms; nevertheless, the transformed state of these cells makes them uniquely susceptible to apoptosis reactivation if resistance is circumvented. Molecular approaches to reengage the apoptotic pathways in cancer have been underway for over two decades. Gratifyingly, BCL-2 antagonists — which drive the intrinsic pathway — are beginning to bear clinical fruit. In contrast, clinical attempts to stimulate the extrinsic pathway with proapoptotic receptor agonists (PARAs) have been disappointing, despite compelling preclinical efficacy with this class of agents. Here, I discuss some of the possible reasons for this translational discrepancy and suggest strategies to overcome it with the next generation of PARAs.
Apoptotic signaling pathways engaged by PARAs that target the death receptors DR4 and DR5.
There are several potential strategies to improve the clinical efficacy of these PARAs. One strategy would be to augment potency by increasing the oligomeric state of Apo2L/TRAIL or the affinity of agonistic anti-DR4 or anti-DR5 antibodies for Fcγ receptors (blue asterisks). Another strategy to improve efficacy would be the implementation of predictive and pharmacodynamic diagnostic biomarkers that might help predict or determine whether a patient’s cancer is sensitive (green asterisks) or resistant (red asterisks) to PARA treatment. A third approach would be to improve synthetic lethality against cancer cells by combining PARAs with pharmacological agents that target various other intracellular signaling components or modulators of the apoptotic pathways (black asterisks). BAX/BAK, BCL-2–associated X protein/BCL-2 antagonist killer 1; BCL-2/XL, B cell lymphoma-2/extra long; BID, BH3-interacting domain death agonist; cFLIP, cellular FLICE-inhibitory protein; CUL3, cullin 3; DISC, death-inducing signaling complex; FADD, Fas-associated death domain; FUT3/6, fucosyltransferase 3/6; GALNT14/3, polypeptide