Reem Ali
Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers
Ali, Reem; Alblihy, Adel; Miligy, Islam M.; Alabdullah, Muslim L.; Alsaleem, Mansour; Toss, Michael S.; Algethami, Mashael; Abdel-Fatah, Tarek; Moseley, Paul; Chan, Stephen; Mongan, Nigel P.; Narayan, Satya; Rakha, Emad A.; Madhusudan, Srinivasan
Authors
Adel Alblihy
Islam M. Miligy
Muslim L. Alabdullah
Mansour Alsaleem
Michael S. Toss
Mashael Algethami
Tarek Abdel-Fatah
Paul Moseley
Stephen Chan
NIGEL MONGAN nigel.mongan@nottingham.ac.uk
Professor of Oncology
Satya Narayan
EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology
SRINIVASAN MADHUSUDAN srinivasan.madhusudan@nottingham.ac.uk
Professor of Medical Oncology
Abstract
Targeting PARP1 [Poly(ADP-Ribose) Polymerase 1] for synthetic lethality is a new strategy for BRCA germ-line mutated or platinum sensitive ovarian cancers. However, not all patients respond due to intrinsic or acquired resistance to PARP1 inhibitor. Development of alternative synthetic lethality approaches is a high priority. DNA polymerase β (Polβ), a critical player in base excision repair (BER), interacts with PARP1 during DNA repair. Here we show that polβ deficiency is a predictor of platinum sensitivity in human ovarian tumours. Polβ depletion not only increased platinum sensitivity but also reduced invasion, migration and impaired EMT (epithelial to mesenchymal transition) of ovarian cancer cells. Polβ small molecular inhibitors (Pamoic acid and NSC666719) were selectively toxic to BRCA2 deficient cells and associated with double-strand breaks (DSB) accumulation, cell cycle arrest and increased apoptosis. Interestingly, PARG [Poly(ADP-Ribose) Glycohydrolase] inhibitor (PDD00017273) [but not PARP1 inhibitor (Olaparib)] was synthetically lethal in polβ deficient cells. Selective toxicity to PDD00017273 was associated with poly (ADP-ribose) accumulation, reduced nicotinamide adenine dinucleotide (NAD+) level, DSB accumulation, cell cycle arrest and increased apoptosis. In human tumours, polβ-PARG co-expression adversely impacted survival in patients. Our data provide evidence that polβ targeting is a novel strategy and warrants further pharmaceutical development in epithelial ovarian cancers.
Citation
Ali, R., Alblihy, A., Miligy, I. M., Alabdullah, M. L., Alsaleem, M., Toss, M. S., …Madhusudan, S. (2021). Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers. Oncogene, 40(14), 2496-2508. https://doi.org/10.1038/s41388-021-01710-y
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 10, 2021 |
Online Publication Date | Mar 5, 2021 |
Publication Date | Apr 8, 2021 |
Deposit Date | Mar 2, 2021 |
Publicly Available Date | Mar 5, 2021 |
Journal | Oncogene |
Print ISSN | 0950-9232 |
Electronic ISSN | 1476-5594 |
Publisher | Nature Publishing Group |
Peer Reviewed | Peer Reviewed |
Volume | 40 |
Issue | 14 |
Pages | 2496-2508 |
DOI | https://doi.org/10.1038/s41388-021-01710-y |
Keywords | Polβ; ovarian cancer; platinum sensitization; EMT; synthetic lethality |
Public URL | https://nottingham-repository.worktribe.com/output/5363394 |
Publisher URL | https://www.nature.com/articles/s41388-021-01710-y |
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