2. Academic Validation
  3. Targeting CDK12 rescues C/EBPβ-mediated platinum and PARP inhibitor resistance in ovarian cancer

Targeting CDK12 rescues C/EBPβ-mediated platinum and PARP inhibitor resistance in ovarian cancer

  • Cell Signal. 2025 Dec 16:112328. doi: 10.1016/j.cellsig.2025.112328.
Jiahong Tan 1,  Wei Dong 1,  Daoqi Wang 2,  Aiqing Tu 1,  Zuheng Wang 1,  Xiaodie Wu 1,  Fen Zhang 1,  Yun Zhu 1,  Li Ren 1,  Ying Ai 1,  Yun Feng 1,  Jie Zhang 3
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, PR China.
  • 2 Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, PR China. Electronic address: [email protected].
  • 3 Department of Obstetrics and Gynecology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, PR China. Electronic address: [email protected].
PMID: 41412562 DOI: 10.1016/j.cellsig.2025.112328
Abstract

Despite multimodality treatment efforts, resistance to platinum and PARP inhibitors represents a primary impediment to improve prognosis of ovarian Cancer. Here, we found that ovarian Cancer tissues had higher C/EBPβ expression compared with normal tissues and high C/EBPβ expression predicted unfavorable survival outcomes. Elevated C/EBPβ expression enhanced cisplatin resistance and olaparib resistance. C/EBPβ could affect DDR signals of ovarian Cancer. CDK12, serving as a C/EBPβ-regulated DDR-related gene, was directly targeted by and bound with C/EBPβ. C/EBPβ could promote CDK12 expression and confer drug tolerance via CDK12. Manipulation of CDK12 could reverse the effects of C/EBPβ. Using CDK12 Inhibitor THZ531 could rescue C/EBPβ-mediated cisplatin resistance and olaparib resistance. Our findings indicated that C/EBPβ is a potent DDR regulator of ovarian Cancer, which directly targets CDK12 and upregulates its expression. High C/EBPβ expression mediates platinum resistance and PARP Inhibitor resistance via CDK12. Targeting C/EBPβ via CDK12 inhibition could rescue drug responsiveness of ovarian Cancer, thereby counteracting platinum and PARP Inhibitor resistance. C/EBPβ could thus be exploited as a candidate prognostic biomarker in ovarian Cancer.

Keywords

Olaparib resistance; Ovarian cancer; Platinum resistance; Prognostic biomarker; Therapeutic target.

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