Saha, Santu;
Rundle, Stuart;
Kotsopoulos, Ioannis C;
Begbie, Jacob;
Howarth, Rachel;
Pappworth, Isabel Y;
Mukhopadhyay, Asima;
... Curtin, Nicola; + view all
(2022)
Determining the Potential of DNA Damage Response (DDR) Inhibitors in Cervical Cancer Therapy.
Cancers
, 14
(17)
, Article 4288. 10.3390/cancers14174288.
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Abstract
Cisplatin-based chemo-radiotherapy (CRT) is the standard treatment for advanced cervical cancer (CC) but the response rate is poor (46–72%) and cisplatin is nephrotoxic. Therefore, better treatment of CC is urgently needed. We have directly compared, for the first time, the cytotoxicity of four 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 a panel of CC cells. All inhibitors alone caused concentration-dependent cytotoxicity. Low ATM and DNA-PKcs levels were associated with greater VE-821 cytotoxicity. Cisplatin induced ATR, CHK1 and WEE1 activity in all of the cell lines. Cisplatin only activated PARP in S-phase cells, but RT activated PARP in the entire population. Rucaparib was the most potent radiosensitiser and VE-821 was the most potent chemosensitiser. VE-821, PF-47736 and MK-1775 attenuated cisplatin-induced S-phase arrest but tended to increase G2 phase accumulation. In mice, cisplatin-induced acute kidney injury was associated with oxidative stress and PARP activation and was prevented by rucaparib. Therefore, while all inhibitors investigated may increase the efficacy of CRT, the greatest clinical potential of rucaparib may be in limiting kidney damage, which is dose-limiting.
| Type: | Article |
|---|---|
| Title: | Determining the Potential of DNA Damage Response (DDR) Inhibitors in Cervical Cancer Therapy |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3390/cancers14174288 |
| Publisher version: | https://doi.org/10.3390/cancers14174288 |
| Language: | English |
| Additional information: | Copyright © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/4.0/). |
| Keywords: | Cervical cancer; cisplatin; radiotherapy; DDR inhibitors; kidney toxicity |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health > Womens Cancer |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10179323 |
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