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单链DNA差距积累是USP1抑制剂敏感性的功能生物标志物

Alexandre A da Costa^1,2, Ozge Somuncu^1,2, Ramya Ravindranathan^1,2

¹Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts.

Cancer research

|June 17, 2024

概括

USP1 抑制剂通过引起DNA 缺口来杀死缺乏 BRCA1 的癌细胞,类似于 PARP 抑制剂. 检测这些单链DNA (ssDNA) 缺口可以预测临床试验中的治疗反应.

科学领域:

遗传学遗传学是一个
分子生物学分子生物学
在瘤学瘤学.

背景情况:

瘤中的BRCA1缺陷会造成合成致死性的脆弱性.
PARP和POLQ抑制剂通过诱导DNA损伤来利用这些漏洞.
USP1抑制剂正在成为BRCA1缺陷癌症的治疗策略.

研究的目的:

研究USP1抑制剂在BRCA1缺乏细胞中的机制.
为了确定USP1抑制是否会诱导单链DNA (ssDNA) 缺口.
评估USP1抑制剂作为治疗反应的预测生物标志物.

主要方法:

用USP1抑制剂治疗BRCA1缺乏细胞和异种移植模型.
对ssDNA差距积累和增殖细胞核抗原 (PCNA) 无处不在的评估.
对药物耐药性和与PARP和POLQ抑制剂的协同效应的评估.
对患者衍生卵巢瘤器官的敏感性和ssDNA差距相关性的分析.

主要成果:

抑制USP1诱导BRCA1缺乏细胞中的ssDNA缺口,与药物敏感性相关.
通过RAD18介导的USP1抑制增加了单基酸PCNA,RAD18.
降低RAD18对USP1抑制剂产生了耐药性,并减少了ssDNA间隙.
抑制USP1克服了PARP抑制剂的耐药性,并与PARP和POLQ抑制剂展现了协同作用.
卵巢瘤器官的敏感性与ssDNA间隙积累相关.

结论:

通过ssDNA间隙积累,USP1抑制剂在BRCA1缺乏细胞中诱导合成致死性.
抑制USP1是一种有前途的治疗策略,有可能克服对其他抑制剂的耐药性.
ssDNA差距评估在临床试验中作为USP1抑制剂疗效的预测生物标志物.

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