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SLX1 Inhibition Enhances Olaparib Sensitivity by Impairing Homologous Recombination Repair in Breast Cancer
Jin-Young Kim1,2, Jeeho Kim1,3, In-Youb Chang4
1Laboratory of Genomic Instability and Cancer Therapeutics, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Republic of Korea.
International Journal of Molecular Sciences
|December 11, 2025
Summary
The structure-specific endonuclease SLX1 regulates homologous recombination (HR) repair and influences Olaparib sensitivity in BRCA1-proficient breast cancer. Targeting SLX1 may restore PARP inhibitor efficacy by inducing HR deficiency.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- PARP inhibitors like Olaparib are effective in BRCA1-deficient breast cancers.
- Efficacy in BRCA1-proficient tumors hinges on homologous recombination (HR) repair status.
Purpose of the Study:
- Identify key regulators of HR in BRCA1-proficient breast cancer.
- Determine the role of SLX1 in Olaparib sensitivity.
Main Methods:
- Assessed SLX1 expression in breast cancer tissues.
- Conducted functional studies on SLX1's role in DNA double-strand break repair.
- Evaluated Olaparib sensitivity in vitro and in vivo following SLX1 modulation.
Main Results:
- SLX1 is upregulated in breast cancer and linked to poor prognosis.
- SLX1 promotes RAD51-mediated HR repair.
- SLX1 depletion sensitizes cells to DNA-damaging agents and Olaparib; overexpression confers resistance.
- SLX1 knockdown synergizes with Olaparib to inhibit tumor growth in vivo.
Conclusions:
- SLX1 is a critical regulator of HR in BRCA1-proficient breast cancer.
- SLX1 is a determinant of Olaparib sensitivity.
- SLX1 represents a potential therapeutic target to enhance PARP inhibitor efficacy.
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