2. Academic Validation
  3. MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC

MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC

  • Cell Biosci. 2023 Sep 27;13(1):178. doi: 10.1186/s13578-023-01117-0.
Xucui Zhuang 1 2,  Rourou Xiao 1 2,  Yu Fu 1 2,  Bin Yang 1 2,  Junpeng Fan 1 2,  Funian Lu 1 2,  Tianyu Qin 1 2,  Xiaohang Yang 1 2,  Xingyuan Hu 1 2,  Jingjing Yin 1 2,  Wenting Li 1 2,  Xiaoyan Kang 1 2,  Gang Chen 1 2,  Dianxing Hu 3 4,  Chaoyang Sun 5 6
Affiliations

Affiliations

  • 1 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. dianxing1989@outlook.com.
  • 4 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. dianxing1989@outlook.com.
  • 5 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. suncydoctor@gmail.com.
  • 6 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. suncydoctor@gmail.com.
PMID: 37759323 DOI: 10.1186/s13578-023-01117-0
Abstract

Background: Although the clinical application of PARP inhibitors has brought hope to ovarian Cancer, the problem of its resistance has become increasingly prominent. Therefore, clinical experts have been focused on finding specific indicators and therapeutic targets that can be used for resistance monitoring of PARP inhibitors.

Results: By cfDNA detecting during Olaparib maintenance therapy in platinum-sensitive relapsed ovarian Cancer, we found the presence of MRE11:p.K464R mutation was strongly associated with acquired Olaparib resistance. Structural analysis revealed that the MRE11:p.K464R mutation is situated at a critical site where the MRE11 protein interacts with other biomolecules, leading to potential structural and functional abnormalities of MRE11 protein. Functionally, MRE11:p.K464R mutation enhanced the tolerance of Olaparib by reducing the DNA damage. Mechanistically, MRE11:p.K464R mutation improved the efficiency of DNA damage repair and induce Olaparib resistance by enhancing its binding activity with the interacting proteins (including RAD50 and RPS3). Among them, the enhanced binding of MRE11:p.K464R mutation to RAD50/RPS3 facilitated non-homologous end joining (NHEJ) repair in tumor cells, thereby expanding the scope of research into acquired resistance to PARP inhibitors.

Conclusions: Our findings provide a theoretical basis for MRE11:p.K464R mutation as a specific indicator of resistance monitoring in Olaparib treatment, and the exploration of its resistance mechanism provides a novel insights for the formulation of combination ther therapies after Olaparib resistance.

Keywords

MRE11:p.K464R mutation; Non-homologous end joining; Olaparib resistance; Ovarian cancer.

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