PPP2R1A mutations cause ATR inhibitor sensitivity in ovarian clear cell carcinoma

IF 7.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Oncogene Pub Date : 2025-02-12 DOI:10.1038/s41388-024-03265-0

James Stewart, Dragomir B. Krastev, Rachel Brough, Diana Zatreanu, Feifei Song, Joseph S. Baxter, Sandhya Sridhar, Jessica Frankum, Asha Konde, William Yang, Syed Haider, John Alexander, Kai Betteridge, Aditi Gulati, Ayoma D. Attygalle, Katherine Vroobel, Rachael Natrajan, Saira Khalique, Theodoros I. Roumeliotis, Jyoti S. Choudhary, Jason Yeung, Andrew J. Wicks, Rebecca Marlow, Susana Banerjee, Stephen J. Pettitt, Andrew N. J. Tutt, Christopher J. Lord

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Abstract

Identification of ARID1A/ATR synthetic lethality led to ATR inhibitor phase II trials in ovarian clear cell carcinoma (OCCC), a cancer of unmet need. Using multiple CRISPR-Cas9 mutagenesis and interference screens, we show that inactivation of protein phosphatase 2A (PP2A) subunits, including PPP2R1A, enhance ATRi sensitivity in ARID1A mutant OCCC. Analysis of a new OCCC cohort indicates that 52% possess oncogenic PPP2R1A p.R183 mutations and of these, one half possessed both ARID1A as well as PPP2R1A mutations. Using CRISPR-prime editing to generate new isogenic models of PPP2R1A mutant OCCC, we found that PPP2R1A p.R183W and p.R183P mutations cause ATRi-induced S phase stress, premature mitotic entry, genomic instability and ATRi sensitivity in OCCC tumour cells. p.R183 mutation also enhanced both in vitro and in vivo ATRi sensitivity in preclinical models of ARID1A mutant OCCC. These results argue for the assessment of PPP2R1A mutations as a biomarker of ATRi sensitivity.

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PPP2R1A突变导致卵巢透明细胞癌中ATR抑制剂敏感性。

ARID1A/ATR合成致死率的鉴定导致了ATR抑制剂在卵巢透明细胞癌（OCCC）的II期试验，这是一种未满足需求的癌症。通过多个CRISPR-Cas9诱变和干扰筛选，我们发现蛋白磷酸酶2A （PP2A）亚基失活，包括PPP2R1A，增强了ARID1A突变OCCC中ATRi的敏感性。一项新的OCCC队列分析表明，52%的人具有致癌PPP2R1A p.R183突变，其中一半的人同时具有ARID1A和PPP2R1A突变。利用CRISPR-prime编辑技术生成PPP2R1A突变体OCCC的新等基因模型，我们发现PPP2R1A p.R183W和p.R183P突变导致OCCC肿瘤细胞中ATRi诱导的S期应激、有丝分裂提前进入、基因组不稳定和ATRi敏感性。在ARID1A突变OCCC的临床前模型中，p.R183突变也增强了体外和体内ATRi敏感性。这些结果支持将PPP2R1A突变作为ATRi敏感性的生物标志物进行评估。

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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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.