2. Academic Validation
  3. Targeting the ATM-TRMT10A-BRCA1 axis confers synthetic lethality to PARP inhibition in metastatic castration-resistant prostate cancer

Targeting the ATM-TRMT10A-BRCA1 axis confers synthetic lethality to PARP inhibition in metastatic castration-resistant prostate cancer

  • Sci Adv. 2025 Oct 10;11(41):eadw7989. doi: 10.1126/sciadv.adw7989.
Ying Yang 1,  Qiang Liu 2,  Xinyan Li 1,  Hua Zhang 3,  Xin Xu 1,  Qi Ma 2,  Somaira Nowsheen 4,  Khaled Aziz 5,  Ye-Xiong Li 1,  Zhenkun Lou 6,  Qiuzi Zhong 7,  Min Deng 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology and Department of Radiation 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 Urology Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
  • 3 Tumor Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
  • 4 Department of Dermatology, University of California, San Diego, San Diego, CA 92122, USA.
  • 5 Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • 6 Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • 7 Department of Radiation Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
PMID: 41071892 DOI: 10.1126/sciadv.adw7989
Abstract

Metastatic castration-resistant prostate Cancer (mCRPC) progresses aggressively and resists existing therapies. Although poly(ADP-ribose) polymerase inhibitors (PARPis) benefit a subset of patients with mCRPC and BRCA1/2 deficiencies, therapeutic options remain limited for those without such mutations. Here, we uncover a critical role for the ATM-TRMT10A-BRCA1 signaling axis in regulating homologous recombination (HR) repair and PARPi sensitivity. We demonstrate that ATM phosphorylates TRMT10A at serine-28 after DNA damage, promoting BRCA1 recruitment and efficient HR repair. TRMT10A deletion disrupts HR repair, sensitizing cells to PARPis. Moreover, TRMT10A is up-regulated in mCRPC through stabilization by USP10. Targeting USP10 with spautin-1 induces TRMT10A degradation and enhances tumor sensitivity to PARPis in cell-derived xenografts and patient-derived xenograft models. These findings identify TRMT10A as a therapeutic vulnerability in mCRPC and demonstrate that combined inhibition of PARP and USP10 offers a promising synthetic lethal strategy for a broader group of patients lacking classical BRCA mutations.

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