High TNF and NF-κB Pathway Dependency Are Associated with AZD5582 Sensitivity in OSCC via CASP8-Dependent Apoptosis.

IF 2 Q3 ONCOLOGY
Annie Wai Yeeng Chai, Yee Hua Tan, Shiyin Ooi, Pei San Yee, Shi Mun Yee, Howard Lightfoot, Syd Barthorpe, Mathew J Garnett, Sok Ching Cheong
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Abstract

Significance: Mechanistically guided drug repurposing has been made possible by systematically integrating pharmacologic and CRISPR-Cas9 screen data. Our study discovers the biomarker and cell death mechanisms underpinning sensitivity toward AZD5582, an antagonist of the inhibitor of apoptosis family protein. Our findings have important implications for improving future trial design for patients with OSCC using this emerging drug class.

高 TNF 和 NF-ĸB 通路依赖性与 OSCC 通过 CASP8 依赖性凋亡对 AZD5582 的敏感性有关。
药物再利用可以加速新型治疗策略的开发。口腔鳞状细胞癌(OSCC)在亚洲人中很常见,而且预后较差。在这里,我们将新生成的 339 种抗癌药物的敏感性数据与主要来自亚洲 OSCC 患者的 21 种细胞系的全基因组 CRISPR-Cas9 基因本质数据进行整合,以确定候选药物的再用途。我们观察到 AZD5582(一种细胞凋亡抑制剂(IAP)家族蛋白的拮抗剂)在一部分 OSCC 细胞中的强效活性,这与 NF-ĸB 通路基因(RNF31、MAP3K7 和 IKBKG)的依赖性有关。我们证实了 AZD5582 在体外的靶向特异性和有效性及其在异种移植模型中抑制细胞生长的能力。此外,我们还发现肿瘤坏死因子(TNF)是 OSCC 对 AZD5582 敏感的关键介质。依赖 CASP8 的细胞凋亡和不依赖 CASP8 的细胞坏死程序介导了 AZD5582 诱导的细胞死亡。总之,通过系统整合药理学和CRISPR数据,我们发现了通过NF-κB和TNF信号通路介导的对AZD5582高度敏感的OSCC亚群。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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