2. Academic Validation
  3. Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer

Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer

  • Nat Commun. 2026 Feb 25;17(1):3142. doi: 10.1038/s41467-026-70001-5.
Yabing Nan # 1 2,  Kunyu Wang # 3,  Menghan Hu # 1,  Qingyu Luo 4,  Xiaowei Wu 5 6,  Xiao Yu 1,  Xuantong Zhou 7,  Li Chen 8,  Bin Li 3,  Zhumei Cui 9,  Zhihua Liu 10 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Gynecological Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 7 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, China.
  • 8 Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 9 Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. [email protected].
  • 10 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 11 Institute of Cancer Research, Henan Academy of Innovations in Medical Sciences, Zhengzhou, Henan, China. [email protected].
  • # Contributed equally.
PMID: 41735312 DOI: 10.1038/s41467-026-70001-5
Abstract

Although poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) as monotherapy or in combination with Other DNA-damaging agents exhibit promising clinical efficacy, the therapeutic responses are usually transient, with subsequent development of acquired resistance posing a significant challenge. Here, through a small-molecule compound screening, we identify elesclomol, a potent copper ionophore, which sensitizes BRCA-proficient ovarian Cancer cells to PARPi by inhibiting activation of the ATR-CHK1 pathway. Mechanistically, we demonstrate that copper directly binds to ATRIP, a critical cofactor of ATR activation, disrupting the ATR-ATRIP interaction, further impairing ATR-mediated DNA damage repair signaling and potentiating PARPi sensitivity. Importantly, we reveal a secondary metabolic vulnerability in PARPi-resistant ovarian Cancer associated with de novo pyrimidine synthesis, suggesting that targeting this pathway as an effective strategy to eradicate drug-adaptive residual tumors and resistant patient-derived xenograft models following ATR and PARP co-inhibition. These findings propose de novo pyrimidine synthesis as an adaptive metabolic vulnerability that can be therapeutically targeted to overcome PARPi resistance in BRCA-proficient ovarian Cancer.

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