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在肌肉侵入性膀癌细胞中,STAG2表达赋予了明显的治疗脆弱性

Sarah R Athans¹, Henry Withers², Aimee Stablewski³

¹Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

|March 2, 2025

概括

流体抗原2 (STAG2) 影响肌肉侵入性膀癌 (MIBC) 的攻击性. 这项研究确定了STAG2依赖的漏洞,揭示了贝佐瑟蒂布和PI-103作为MIBC患者潜在的精确疗法.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
癌症治疗方法癌症治疗方法

背景情况:

流体抗原2 (STAG2) 表达与侵袭性肌肉侵入性膀癌 (MIBC) 和不良结果相关.
在膀癌发病过程中STAG2的确切作用及其治疗含义在很大程度上仍未被描述.

研究的目的:

根据STAG2表达水平,识别MIBC细胞中可向的治疗漏洞.
阐明STAG2在膀癌信号通路中的功能作用.

主要方法:

使用CRISPR-Cas9.9生成STAG2野生类型 (WT) 和淘汰 (KO) 同源细胞系.
对这些细胞系选了312种抗癌化合物,并分析了DepMap数据库中的药物敏感性数据.
进行了RNA-seq分析和与向抑制剂和西斯的协同实验.

主要成果:

STAG2 KO使细胞对PLK1抑制剂rigosertib敏感,但对MEK抑制剂TAK-733和PI3K抑制剂PI-103有保护.
较低的STAG2mRNA表达与对ATR和CHK抑制剂的敏感性相关.
STAG2 KO 细胞对ATR 抑制剂贝佐瑟蒂布的敏感性增加,而WT 细胞对PI3K 抑制剂PI-103的敏感性增加.
在MIBC细胞中,贝尔佐瑟蒂布与思普拉丁表现出协同性细胞毒性.

结论:

在膀癌中,STAG2在调节PI3K信号传递方面发挥着新的作用.
伯佐瑟蒂布,PI-103,以及它们与西斯普拉丁的结合,代表了STAG2表达分层的MIBC患者的潜在精准医学策略.

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