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Peer-reviewedCC BY 4.0Cell Cycle

Targeting G2/M checkpoint vulnerability in homologous recombination-proficient tumors: lessons from ovarian cancer models

  • Qian Xi1,2
  • Akiko Kunita3,4
  • Saeko Nagai5
  • Anh Quynh Duong5
  • Masanori Kawakami6
  • Katsutoshi Oda1
6 affiliations
  1. 1Division of Integrative Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  2. 2Department of Gynecological Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
  3. 3Next-Generation Precision Medicine Development Laboratory, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  4. 4Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  5. 5Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  6. 6Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Abstract

Cell cycle dysregulation is a hallmark of cancer; however, tumors retaining homologous recombination (HR)-proficiency remain a major challenge. Although PARP inhibitors effectively target HR-deficient cancers, targeted therapies for BRCA1/2-wild-type, HR-proficient tumors are limited. High-grade serous ovarian cancer, approximately half of which is HR-proficient, illustrates that HR proficiency, together with replication stress and checkpoint dependence, may represent both a mechanism of therapeutic resistance and a druggable dependency on checkpoint-coupled DNA repair. This review synthesizes evidence that targeting either PLK1 or WEE1 independently exposes this vulnerability. PLK1 and WEE1 inhibition engage distinct mechanisms: PLK1 inhibition disrupts spindle assembly and HR competence, whereas WEE1 inhibition amplifies replication stress and forces premature mitotic entry. Nevertheless, both ultimately converge to compromise HR-associated repair, promote unresolved DNA damage, and trigger lethal mitotic catastrophe. Finally, we discuss biomarker-unselected trial failures, functional and replication stress-based patient stratification, and rational combinations with DNA-damaging agents and immunotherapy.

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Cite

BibTeXRIS
BibTeX
@article{xi2026targeting,
  title = {{Targeting G2/M checkpoint vulnerability in homologous recombination-proficient tumors: lessons from ovarian cancer models}},
  author = {Qian Xi and Akiko Kunita and Saeko Nagai and Anh Quynh Duong and Masanori Kawakami and Katsutoshi Oda},
  journal = {Cell Cycle},
  year = {2026},
  month = oct,
  doi = {10.1080/15384101.2026.2751743},
  url = {https://doi.org/10.1080/15384101.2026.2751743},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Targeting G2/M checkpoint vulnerability in homologous recombination-proficient tumors: lessons from ovarian cancer models
AU  - Qian Xi
AU  - Akiko Kunita
AU  - Saeko Nagai
AU  - Anh Quynh Duong
AU  - Masanori Kawakami
AU  - Katsutoshi Oda
PY  - 2026
DA  - 2026/10/27
JO  - Cell Cycle
DO  - 10.1080/15384101.2026.2751743
UR  - https://doi.org/10.1080/15384101.2026.2751743
AB  - Cell cycle dysregulation is a hallmark of cancer; however, tumors retaining homologous recombination (HR)-proficiency remain a major challenge. Although PARP inhibitors effectively target HR-deficient cancers, targeted therapies for BRCA1/2-wild-type, HR-proficient tumors are limited. High-grade serous ovarian cancer, approximately half of which is HR-proficient, illustrates that HR proficiency, together with replication stress and checkpoint dependence, may represent both a mechanism of therapeutic resistance and a druggable dependency on checkpoint-coupled DNA repair. This review synthesizes evidence that targeting either PLK1 or WEE1 independently exposes this vulnerability. PLK1 and WEE1 inhibition engage distinct mechanisms: PLK1 inhibition disrupts spindle assembly and HR competence, whereas WEE1 inhibition amplifies replication stress and forces premature mitotic entry. Nevertheless, both ultimately converge to compromise HR-associated repair, promote unresolved DNA damage, and trigger lethal mitotic catastrophe. Finally, we discuss biomarker-unselected trial failures, functional and replication stress-based patient stratification, and rational combinations with DNA-damaging agents and immunotherapy.
SN  - 1538-4101
SN  - 1551-4005
ER  -