| Autor: |
Alpesh Shah, Vanessa Martins, Simon S. McDade, Emma M. Kerr, Tomoko Smyth, Phillip D. Dunne, Vicky M. Coyle, Mark Lawler, Daniel B. Longley, Katie Stott, C. Latimer, William J. McDaid, Joanne M. Munck, Jennifer Fox, Christopher McCann, Tamas Sessler, Nyree Crawford |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.11.20.391680 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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