Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer.
Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer.
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DOI：
10.1158/1535-7163.mct-20-1050
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发表时间：
2021-09
影响因子：
5.7
通讯作者：
Longley DB
中科院分区：
文献类型：
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作者：
Crawford N;Stott KJ;Sessler T;McCann C;McDaid W;Lees A;Latimer C;Fox JP;Munck JM;Smyth T;Shah A;Martins V;Lawler M;Dunne PD;Kerr EM;McDade SS;Coyle VM;Longley DB
凋亡抑制蛋白（Inhibitors of apoptosis proteins，IAPs）是一类细胞内的蛋白质，在调节细胞死亡、炎症和免疫等方面具有重要作用。在这里，我们研究了IAP在结直肠癌中的临床和治疗相关性。我们发现，cIAP 1和cIAP 2（而不是XIAP）的表达升高与微卫星稳定（MSS）的III期结直肠癌患者接受5-氟尿嘧啶（5 FU）为基础的辅助化疗的不良预后显着相关，这表明他们参与促进化疗耐药性。一种新型IAP拮抗剂tolinapant（ASTX 660）在结直肠癌模型中有效且快速地下调cIAP 1，证明了其稳健的靶向疗效。在与TNFα共培养以模拟炎性肿瘤微环境的细胞中，在结直肠癌细胞系模型中，tolinapant诱导了caspase-8依赖性细胞凋亡;然而，由于caspase-8旁系同源物FLIP和caspase-10的抑制，细胞凋亡的程度有限。重要的是，在体外和体内人结直肠癌和鼠类器官模型中，FOLFOX增强了托立那普诱导的细胞凋亡，这是由于（至少部分）FOLFOX诱导的I类组蛋白脱乙酰酶（HDAC）下调，导致FLIP结合伴侣Ku 70乙酰化和FLIP下调。此外，FOLFOX的作用可以使用临床相关的I类HDAC抑制剂恩替司他进行表型模拟，恩替司他也诱导Ku 70的乙酰化和FLIP下调。进一步的分析显示，caspase-8敲除RIPK 3阳性结直肠癌模型对托利奈坦诱导的坏死性凋亡敏感，这种作用可以在使用临床相关的caspase抑制剂emricasan的caspase-8熟练模型中利用。我们的研究为立即临床探索tolinapant联合FOLFOX治疗cIAP 1/2表达升高的预后不良的MSS结直肠癌提供了证据。
Inhibitors of apoptosis proteins (IAPs) are intracellular proteins, with important roles in regulating cell death, inflammation, and immunity. Here, we examined the clinical and therapeutic relevance of IAPs in colorectal cancer. We found that elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in patients with microsatellite stable (MSS) stage III colorectal cancer treated with 5-fluorouracil (5FU)–based adjuvant chemotherapy, suggesting their involvement in promoting chemoresistance. A novel IAP antagonist tolinapant (ASTX660) potently and rapidly downregulated cIAP1 in colorectal cancer models, demonstrating its robust on-target efficacy. In cells co-cultured with TNFα to mimic an inflammatory tumor microenvironment, tolinapant induced caspase-8–dependent apoptosis in colorectal cancer cell line models; however, the extent of apoptosis was limited because of inhibition by the caspase-8 paralogs FLIP and, unexpectedly, caspase-10. Importantly, tolinapant-induced apoptosis was augmented by FOLFOX in human colorectal cancer and murine organoid models in vitro and in vivo, due (at least in part) to FOLFOX-induced downregulation of class I histone deacetylases (HDAC), leading to acetylation of the FLIP-binding partner Ku70 and downregulation of FLIP. Moreover, the effects of FOLFOX could be phenocopied using the clinically relevant class I HDAC inhibitor, entinostat, which also induced acetylation of Ku70 and FLIP downregulation. Further analyses revealed that caspase-8 knockout RIPK3-positive colorectal cancer models were sensitive to tolinapant-induced necroptosis, an effect that could be exploited in caspase-8–proficient models using the clinically relevant caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX in poor prognosis MSS colorectal cancer with elevated cIAP1/2 expression.