Full Text | PDF

Theranostics 2021; 11(17):8350-8361. doi:10.7150/thno.51456 This issue Cite

Research Paper

Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers

Reem Ali^1*, Muslim Alabdullah^1,2*, Mashael Algethami^1#, Adel Alblihy^1,3#, Islam Miligy², Ahmed Shoqafi¹, Katia A. Mesquita¹, Tarek Abdel-Fatah⁴, Stephen YT Chan⁴, Pei Wen Chiang⁵, Nigel P Mongan^6,7, Emad A Rakha², Alan E Tomkinson⁸, Srinivasan Madhusudan^1,4✉

1. Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham NG7 3RD, UK.
2. Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK.
3. Medical Center, King Fahad Security College (KFSC), Riyadh 11461, Saudi Arabia.
4. Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham NG5 1PB, UK.
5. Department of Obstetrics & Gynaecology, Queens Medical Centre, Nottingham University Hospitals, Nottingham NG7 2UH, UK.
6. Faculty of Medicine and Health Sciences, Centre for Cancer Sciences, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire LE12 5RD, UK
7. Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065, USA
8. Department of Internal Medicine, Division of Molecular Medicine, Health Sciences Center, The University of New Mexico, Albuquerque, NM 87102, USA.
^* Joint first authors
^# Joint second authors

✉ Corresponding author: Professor Srinivasan Madhusudan, Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham NG7 3RD, UK. Telephone: +44(0)115 823 1850, Fax: +44(0)115 823 1849, E-Mail: srinivasan.madhusudanac.uk More

Abstract

Rationale: The human ligases (LIG1, LIG3 and LIG4) are essential for the maintenance of genomic integrity by catalysing the formation of phosphodiester bonds between adjacent 5′-phosphoryl and 3′-hydroxyl termini at single and double strand breaks in duplex DNA molecules generated either directly by DNA damage or during replication, recombination, and DNA repair. Whether LIG1, LIG3 and LIG4 can influence ovarian cancer pathogenesis and therapeutics is largely unknown.

Methods: We investigated LIG1, LIG3 and LIG4 expression in clinical cohorts of epithelial ovarian cancers [protein level (n=525) and transcriptional level (n=1075)] and correlated to clinicopathological features and survival outcomes. Pre-clinically, platinum sensitivity was investigated in LIG1 depleted ovarian cancer cells. A small molecule inhibitor of LIG1 (L82) was tested for synthetic lethality application in XRCC1, BRCA2 or ATM deficient cancer cells.

Results: LIG1 and LIG3 overexpression linked with aggressive phenotypes, platinum resistance and poor progression free survival (PFS). In contrast, LIG4 deficiency was associated with platinum resistance and worse PFS. In a multivariate analysis, LIG1 was independently associated with adverse outcome. In ovarian cancer cell lines, LIG1 depletion increased platinum cytotoxicity. L82 monotherapy was synthetically lethal in XRCC1 deficient ovarian cancer cells and 3D-spheroids. Increased cytotoxicity was linked with accumulation of DNA double strand breaks (DSBs), S-phase cell cycle arrest and increased apoptotic cells. L82 was also selectively toxic in BRCA2 deficient or ATM deficient cancer cells and 3D-spheroids.

Conclusions: We provide evidence that LIG1 is an attractive target for personalization of ovarian cancer therapy.

Keywords: Ovarian cancer, DNA repair, LIG1, LIG3, LIG4, LIG1 inhibitor, Prognostics, Predictive bimarker, Synthetic lethality

Citation styles

©2024 Ivyspring International Publisher. Terms of use