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Here, we define PTEN deficiency as a predictive biomarker for the response to ATR inhibition, as monotherapy and in combination with PARP inhibition or gemcitabine. In response to ATR inhibition and compared with PTEN-proficient cells, PTEN-deficient cells are prone to (a) uncoupling of DNA polymerase and helicase activities, leading to excessive ssDNA and replication stress; (b) cytoplasmic sequestration of checkpoint kinase 1 (CHK1), compromising cell-cycle checkpoint control with reduced compensatory effects by ataxia-telangiectasia mutated (ATM) and DNA\u2013dependent proteinase K (DNA-PK), leading to mitotic catastrophe; and (c) reduced DNA repair protein RAD51 homolog 1 (RAD51) recruitment, exacerbating replication fork instability, also leading to lethality. Retrospective analyses revealed that patients with HGSOC who expressed low PTEN levels experienced greater clinical benefit on ATR inhibitor\u2013based trials than did those with high PTEN levels. These results justify prospective trials evaluating ATR inhibition as a therapeutic strategy for PTEN-deficient tumors.<\/jats:p>\n                  <jats:p\/>\n                  <jats:p>Hao et al. have demonstrated that PTEN deficiency confers sensitivity to ATR inhibitor-based treatment in preclinical models and clinical trials of high-grade serous ovarian cancer.<\/jats:p>","DOI":"10.1172\/jci197645","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T16:00:34Z","timestamp":1783440034000},"source":"Crossref","is-referenced-by-count":0,"title":["PTEN deficiency confers sensitivity to ATR inhibitor\u2013based treatment in high-grade serous ovarian cancer"],"prefix":"10.1172","volume":"136","author":[{"given":"Jie","family":"Hao","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI), Boston, Massachusetts, USA."},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bose","family":"Kochupurakkal","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI), Boston, Massachusetts, USA."},{"name":"Center for DNA Damage and Repair, DFCI, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy B.","family":"Branigan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI), Boston, Massachusetts, USA."},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozge Sezin","family":"Somuncu","sequence":"additional","affiliation":[{"name":"Center for DNA Damage and Repair, DFCI, Boston, Massachusetts, USA."},{"name":"Department of Radiation Oncology, DFCI and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI), Boston, Massachusetts, USA."},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heta","family":"Jadhav","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI), Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre Andr\u00e9 B. 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