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ResearchIn-Press PreviewCell biologyClinical ResearchOncology Open Access | 10.1172/JCI197645

PTEN deficiency confers sensitivity to ATR inhibitor-based treatment in high-grade serous ovarian cancer

Jie Hao,1 Bose Kochupurakkal,1 Timothy B. Branigan,1 Ozge Sezin Somuncu,2 Renyan Liu,1 Heta Jadhav,1 Alexandre Andre B.A. da Costa,2 Yuqing Jiao,1 Jenny Z. Yu,1 David B. Martignetti,2 Golbahar Sadatrezaei,2 Sirisha Mukkavalli,2 Prafulla C. Gokhale,3 Su-Chun Cheng,4 Steven J. Skates,5 Dimitrios Nasioudis,6 Panagiotis A. Konstantinopoulos,1 Joyce F. Liu,1 Stephanie L. Gaillard,7 Robert L. Giuntoli II,6 Lainie P. Martin,6 Janos L. Tanyi,6 Nawar Latif,6 Ian S. Heller,6 Fiona Simpkins,6 Kalindi Parmar,2 Alan D. D'Andrea,2 and Geoffrey I. Shapiro1

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Hao, J. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Kochupurakkal, B. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Branigan, T. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Somuncu, O. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Liu, R. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Jadhav, H. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by da Costa, A. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Jiao, Y. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Yu, J. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Martignetti, D. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Mukkavalli, S. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Cheng, S. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Skates, S. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Nasioudis, D. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Konstantinopoulos, P. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Liu, J. in: PubMed | Google Scholar |

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Martin, L. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Tanyi, J. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Latif, N. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Heller, I. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Simpkins, F. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Parmar, K. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by D'Andrea, A. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, United States of America

3Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Data Science, Dana-Farber Cancer Institute and Harvard H.T. Chan School of Public Health, Boston, United States of America

5Massachusetts General Hospital Biostatistics and Harvard Medical School, Boston, United States of America

6Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

7Departments of Oncology and Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Shapiro, G. in: PubMed | Google Scholar |

Published July 7, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI197645.
Copyright © 2026, Hao et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 7, 2026 - Version history
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Abstract

ATR inhibition is under evaluation for treatment of high-grade serous ovarian cancer (HGSOC) to reverse acquired resistance to poly (ADP-ribose) polymerase (PARP) inhibition and to exacerbate chemotherapy-induced replicative stress. Here, we define PTEN deficiency as a predictive biomarker for response to ATR inhibition, as monotherapy and in combination with PARP inhibition or gemcitabine. In response to ATR inhibition and compared to PTEN-proficient cells, PTEN-deficient cells are prone to (1) uncoupling of DNA polymerase and helicase activities, leading to excessive single-stranded DNA and replication stress; (2) cytoplasmic sequestration of CHK1, compromising cell cycle checkpoint control with reduced compensatory effects by ATM and DNA-PK, leading to mitotic catastrophe; and (3) reduced RAD51 recruitment, exacerbating replication fork instability, also leading to lethality. Retrospective analyses demonstrate that patients with HGSOC expressing low PTEN levels experience greater clinical benefit on ATR inhibitor-based trials than those with high levels. These results justify prospective trials evaluating ATR inhibition as a therapeutic strategy for PTEN-deficient tumors.

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