<scp>IAP</scp> Antagonists Selectively Eliminate Therapy‐Induced Senescent Cancer Cells via <scp>TNFα</scp> ‐Independent Apoptosis

Therapy-induced senescence (TIS) is a state in which cancer cells enter growth arrest following chemotherapy. TIS cancer cells influence the tumor microenvironment through their senescence-associated secretory phenotype and independently acquire stem-like properties, both of which contribute to increased aggressiveness and tumor relapse. Here, we show that AZD5582 and AT406, potent antagonists of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP2) and X-linked inhibitor of apoptosis protein (XIAP), selectively eliminated HCT116 and RKO cells that had undergone senescence following treatment with a chemotherapeutic agent such as trifluridine, camptothecin, or doxorubicin. This elimination occurred via apoptosis associated with caspase 8 activation. These TIS cancer cells produced and secreted tumor necrosis factor α (TNFα); however, the selective cytotoxicity of IAP antagonists toward TIS cells was unexpectedly largely TNFα-independent. Consistently, the same IAP antagonists sensitized cancer cells treated with nutlin-3a, which induces senescence without TNFα production. Depletion of both cIAP1 and XIAP recapitulated the selective cytotoxicity against both TIS and nutlin-3a-induced senescent cancer cells. At physiological concentrations, TNFα sensitized non-senescent, proliferating cancer cells, but not TIS and nutlin-3a-induced senescent cancer cells, to apoptosis in the presence of IAP antagonists. Collectively, these findings suggest that IAP antagonists could serve as effective concomitant agents to TIS-inducing chemotherapy that promotes TNFα secretion within tumors, functioning not only as TNFα-independent senolytics but also as potentiators of TNFα-mediated apoptosis in adjacent non-senescent, proliferating cancer cells.