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Determining the Potential of DNA Damage Response (DDR) Inhibitors in Cervical Cancer Therapy
Santu Saha1, Stuart Rundle2, Ioannis C Kotsopoulos3
1Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Cancers
|September 9, 2022
Summary
This study investigated DNA damage response inhibitors for cervical cancer (CC) treatment. Rucaparib showed potential in reducing cisplatin
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Cisplatin-based chemo-radiotherapy (CRT) is standard for advanced cervical cancer (CC), but has limited efficacy (46-72% response) and significant nephrotoxicity.
- There is an urgent need for improved CC treatments that enhance CRT effectiveness and mitigate side effects.
Purpose of the Study:
- To evaluate the cytotoxicity of four DNA damage response (DDR) inhibitors—rucaparib (PARPi), VE-821 (ATRi), PF-477736 (CHK1i), and MK-1775 (WEE1i)—as single agents and in combination with cisplatin and radiotherapy (RT) in CC cells.
- To assess the potential of these inhibitors in overcoming treatment resistance and reducing cisplatin-induced toxicity.
Main Methods:
- Cytotoxicity assays were performed on a panel of CC cell lines treated with individual DDR inhibitors, cisplatin, and RT.
- Drug sensitivity was correlated with baseline DNA-PKcs and ATM levels.
- Cell cycle progression and DNA damage markers were analyzed post-treatment.
- The protective effect of rucaparib against cisplatin-induced nephrotoxicity was evaluated in a mouse model.
Main Results:
- All DDR inhibitors exhibited concentration-dependent cytotoxicity as single agents.
- Rucaparib demonstrated potent radiosensitizing effects, while VE-821 was the most effective chemosensitizer.
- VE-821, PF-47736, and MK-1775 modulated cell cycle arrest induced by cisplatin, affecting S and G2 phases.
- Rucaparib administration prevented cisplatin-induced acute kidney injury in mice, linked to reduced oxidative stress and PARP activation.
Conclusions:
- All investigated DDR inhibitors show promise in enhancing the efficacy of chemoradiotherapy for cervical cancer.
- Rucaparib exhibits significant potential in mitigating cisplatin-induced nephrotoxicity, a critical dose-limiting side effect.
- VE-821, PF-47736, and MK-1775 may offer alternative strategies for improving CC treatment response through modulation of cell cycle checkpoints.
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