Repression of PRMT activities sensitize human homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment

Elife. 2026 Feb 3:13:RP99225. doi: 10.7554/eLife.99225.

Youyou Zhang ^# ¹ ², Mu Xu ^# ¹, Jiao Yuan ¹, Zhongyi Hu ¹, Junjie Jiang ¹, Yanrong Sun ¹, Jie Huang ¹, Yuxin Wang ¹, Bingwei Wang ¹, Jianfeng Shen ¹, Meixiao Long ³, Yi Fan ⁴ ⁵, Kathleen T Montone ⁶, Janos Tanyi ² ⁴ ⁷, Sarah H Kim ² ⁴, Omid Tavana ⁸, Robert H Vonderheide ⁴, Ho Man Chan ⁸, Susan Domchek ⁴ ⁹ ¹⁰, Lin Zhang ¹ ² ⁴, Xiaowen Hu ¹ ²

Affiliations

1 Center for Women's Health and Reproductive Medicine, University of Pennsylvania, Philadelphia, United States.
2 Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, United States.
3 Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, United States.
4 Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States.
5 Department of Radiation Oncology, University of Pennsylvania, Philadelphia, United States.
6 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States.
7 Center for Gynecologic Cancer Immunotherapies, University of Pennsylvania, Philadelphia, United States.
8 Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, United States.
9 Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, United States.
10 Basser Center for BRCA, University of Pennsylvania, Philadelphia, United States.
# Contributed equally.

PMID: 41632514 DOI: 10.7554/eLife.99225

Abstract

Therapeutic epigenetic modulation is currently being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARP inhibitors. To broaden its clinical applicability and identify more effective combination strategies, we conducted a drug screen combining PARP inhibitors with 74 well-characterized epigenetic modulators targeting five major classes of epigenetic Enzymes. Notably, both type I PRMT inhibitors and PRMT5 inhibitors scored highly in combination efficacy and clinical prioritization. PRMT inhibition significantly enhanced PARP inhibitor-induced DNA damage in human HR-proficient ovarian and breast Cancer cells. Mechanistically, PRMT suppression downregulates DNA damage repair genes and BRCAness-associated pathways, while also modulating intrinsic innate immune responses within Cancer cells. Integrative analysis of large-scale genomic and functional datasets from TCGA and DepMap further supports PRMT1, PRMT4, and PRMT5 as promising therapeutic targets in oncology. Importantly, dual inhibition of PRMT1 and PRMT5 synergistically sensitizes tumors to PARP inhibitors. Collectively, our findings provide strong rationale for the clinical development of PRMT and PARP Inhibitor combinations in HR-proficient ovarian and breast cancers.

Keywords

PARP inhibitor; PRMT inhibitor; cancer biology; cancer treatment; mouse.

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