2. Academic Validation
  3. LEF1 confers resistance to DNA-damaging chemotherapies through upregulation of PARP1 and NUMA1 in ovarian cancer

LEF1 confers resistance to DNA-damaging chemotherapies through upregulation of PARP1 and NUMA1 in ovarian cancer

  • Oncogene. 2025 Sep 10. doi: 10.1038/s41388-025-03561-3.
Lin Huang # 1,  Mengna Zhu # 1,  Mengqing Chen # 1,  Feiquan Ying 1,  Qiulei Wu 1,  Pan Liu 1,  Wenhan Li 1,  Guoqing Li 1,  Yuewen Gao 1,  Shuyan Yi 1,  Wenwen Wang 1,  Yiping Wen 1,  Si Sun 2,  Jing Cai 3,  Man Xiao 4
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. sisun@hust.edu.cn.
  • 3 Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. jingcai@hust.edu.cn.
  • 4 Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. d201478266@alumni.hust.edu.cn.
  • # Contributed equally.
PMID: 40931049 DOI: 10.1038/s41388-025-03561-3
Abstract

Resistance to platinum-based drugs and PARP inhibitors (PARPi) is the leading cause of treatment failure in epithelial ovarian Cancer (EOC). This study aimed to identify resistance mechanisms shared by both. Using bioinformatic analyses, EOC tissues, primary tumor cells and organoids, and chemoresistant cell lines, we identified lymphoid enhancer-binding factor 1 (LEF1) as a candidate, whose expression was increased in both platinum-resistant and PARPi-resistant tumors. Moreover, LEF1 deficiency increased EOC cell sensitivity to cisplatin and PARPi in vitro and in vivo. Mechanistically, LEF1 knockdown promoted double-strand breaks and significantly impaired both homologous recombination and nonhomologous end joining by directly downregulating the transcription of PARP1 and NUMA1. In addition, the LEF1 inhibitor niclosamide increased ovarian Cancer sensitivity to Cisplatin and PARPi in patient-derived organoids and Niraparib-resistant cell lines. These findings indicate that LEF1 is a potential therapeutic target for overcoming resistance to chemotherapy based on platinum and PARPi in EOC.

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