Figure 2.

Small-molecule inhibitors promote cell death in HNSCC cells. (1) In HNSCC cells, anti-apoptotic BCL-2 family proteins are often overexpressed. The BH3-mimetic compound, ABT-263, inhibits the function of these proteins by binding to their hydrophobic pockets. Pro-apoptotic BCL-2 family proteins (BAX, BAK) release to initiate the release of cytochrome c, following downstream caspase cascades that result in apoptosis. (2) Survivin, an Inhibitor of Apoptosis Protein (IAP), inhibits Smac that is released from the mitochondria followed by cell death stimuli. Survivin is also often overexpressed in HNSCC, which can be inhibited by the survivin inhibitor, YM155. (3) Caspase-8, which is activated by extrinsic death receptors (e.g., FAS, TNFR) to induce apoptosis, is mutated and inactivated in ~10% of HNSCC. When caspase-8 is inactivated, RIPK3-mediated necroptosis can be promoted. Necroptosis by radiation is enhanced when combined with a SMAC mimetic, birinapant.