GPX4 Inhibition Enhances the Antitumor Effect of PARP Inhibitor on Homologous Recombination Proficient Ovarian Cancer Cells

Jiaxin Gu; Senmi Qian; Fangfang Qian; Xiaodong Wu; Lifeng Chen; Xiaojing Chen; Zhuoye Chen; Feifei Song; Mengxia Zheng; Lingfang Wang; Xiaodong Cheng

doi:10.2174/0115680096334278240821100404

GPX4 Inhibition Enhances the Antitumor Effect of PARP Inhibitor on Homologous Recombination Proficient Ovarian Cancer Cells

Curr Cancer Drug Targets. 2024 Aug 26. doi: 10.2174/0115680096334278240821100404. Online ahead of print.

Authors

Jiaxin Gu^{1

2}, Senmi Qian^{1

2}, Fangfang Qian^{1

3}, Xiaodong Wu^{1

2}, Lifeng Chen⁴, Xiaojing Chen¹, Zhuoye Chen^{1

2}, Feifei Song^{1

2}, Mengxia Zheng¹, Lingfang Wang^{1

2}, Xiaodong Cheng^{1

2}

Affiliations

¹ Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
² Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Hangzhou, Zhejiang, China.
³ Department of Gynecology, Hangzhou Third People's Hospital, Hangzhou, Zhejiang, China.
⁴ Department of Gynecology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

PMID: 39192643
DOI: 10.2174/0115680096334278240821100404

Abstract

Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are now widely used in BRCA1/2 mutation or homologous recombination (HR) deficiency ovarian cancer but have limited efficacy in HR-proficient patients. GPX4 is a key regulator of ferroptosis and has been proven to be associated with multiple drug sensitivities. As a molecule that regulates the sensitivity of multiple drugs, the relationship between GPX4 and the efficacy of PARPi in HR-proficient ovarian cancer has not been elucidated.

Methods: In this study, siRNA transfection was used to regulate the expression of GPX4. The effect of GPX4 inhibition on HR-proficient ovarian cancer was determined by CCK-8 assay and flow cytometry. Immunofluorescence and comet assays were used to reflect DNA dam-age. ROS production was measured using DCFH-DA and flow cytometry. The combination index of PARP inhibitors and RSL3 was calculated using CompuSyn software based on Chou-Talalay methodology.

Results: GPX4 inhibition confers HR-proficient ovarian cancer cells sensitive to PARPi due to ROS generation and oxidative stress caused by DNA double-strand breakage. The combina-tion of olaparib and niraparib with GPX4 inhibitor RSL3 also showed a synergistic effect.

Conclusion: Combining GPX4 inhibition with PARP inhibitors resulted in a notable increase in DNA damage, ultimately causing the death of cancer cells with proficient HR pathways. Our findings may provide new therapeutic options for HR-proficient patients to benefit from PARP inhibitors and improve outcomes.

Keywords: GPX4; Ovarian cancer; PARP inhibitors; homologous recombination deficiency (HRD)..