PT - JOURNAL ARTICLE AU - Nyree Crawford AU - Katie Stott AU - Tamas Sessler AU - Christopher McCann AU - William McDaid AU - Cheryl Latimer AU - Jennifer Fox AU - Joanne M Munck AU - Tomoko Smyth AU - Alpesh Shah AU - Vanessa Martins AU - Mark Lawler AU - Philip Dunne AU - Emma Kerr AU - Simon S McDade AU - Vicky Coyle AU - Daniel B Longley TI - Clinical positioning of the IAP antagonist tolinapant (ASTX660) in colorectal cancer AID - 10.1101/2020.11.20.391680 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.11.20.391680 4099 - http://biorxiv.org/content/early/2020/11/20/2020.11.20.391680.short 4100 - http://biorxiv.org/content/early/2020/11/20/2020.11.20.391680.full AB - Cancer cells frequently express elevated levels of Inhibitor of Apoptosis Proteins (IAPs): cIAPI, cIAP2 and XIAP. Elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in microsatellite stable (MSS) stage-III colorectal cancer (CRC) patients treated with adjuvant chemotherapy, suggesting their involvement in promoting resistance. Preclinical analysis of the IAP inhibitor tolinapant in CRC cell lines demonstrated robust on-target effects and caspase-8-dependent apoptosis that was inhibited by the caspase-8 paralogs FLIP and, unexpectedly, caspase-10. Importantly, tolinipant-induced apoptosis was augmented by standard-of-care chemotherapy (FOLFOX) in CRC disease models, due (at least in part) to FOLFOX-induced downregulation of Class-I histone deacetylases, leading to acetylation of the FLIP-binding partner Ku70 and downregulation of FLIP. Moreover, this effect could be phenocopied using a Class-I HDAC inhibitor. Further analyses revealed that caspase-8-knockout RIPK3-positive CRC models were sensitive to tolinostat-induced necroptosis, an effect that could be exploited with the FDA-approved caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX chemotherapy in poor prognosis MSS CRC with elevated cIAP1/2 expression.