IAP antagonists potentiate TNFα-triggered apoptosis but selectively eliminate senescent tumor cells independently of TNFα

Abstract

Therapy-induced senescence (TIS) is a state of cell division arrest induced by chemotherapy that blocks tumor growth. TIS tumor cells affect the tumor microenvironment through their senescence-associated secretory phenotype and independently acquire stemness, which makes them more aggressive and causes relapse once they regrow. To eradicate tumors by chemotherapy, long-lived TIS tumor cells must be efficiently eliminated. Here, we show that AZD5582 and AT406, which are potent antagonists of inhibitor of apoptosis proteins (IAP antagonists) that suppress the activities of cellular inhibitor of apoptosis protein 1 (cIAP1), cellular inhibitor of apoptosis protein 2 (cIAP2), and X-linked inhibitor of apoptosis protein (XIAP), selectively induced apoptosis mediated by caspase 8 and effector caspases in TIS tumor cells, which produced and secreted tumor necrosis factor (TNF). However, these IAP antagonists were still selectively cytotoxic to TIS tumor cells even when TNF was absent (TNF-knockout cells) or neutralized (by a neutralizing antibody), indicating they have TNF-independent senolytic activity. Consistently, these IAP antagonists also sensitized tumor cells that had been induced to become senescent by nutlin-3a, which activates p53 but does not trigger TNF production. Furthermore, TNF sensitized tumor cells treated with these IAP antagonists irrespective of their senescence status. Collectively, these data indicate that IAP antagonists that inhibit cIAPs and XIAP not only potentiate TNF-triggered apoptosis but also have TNF-independent senolytic activity. We propose that IAP antagonists are good concomitant drugs of chemotherapy that induces TIS, not only as senolytic drugs but also as sensitizers of adjacent non-senescent tumor cells mediated by paracrine TNF.