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

Ali, Reem; Alabdullah, Muslim; Algethami, Mashael; Alblihy, Adel; Miligy, Islam; Shoqafi, Ahmed; Mesquita, Katia A.; Abdel-Fatah, Tarek; Chan, Stephen Y.T.; Chiang, Pei Wen; Mongan, Nigel P.; Rakha, Emad A.; Tomkinson, Alan E.; Madhusudan, Srinivasan

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.

Citation

Ali, R., Alabdullah, M., Algethami, M., Alblihy, A., Miligy, I., Shoqafi, A., Mesquita, K. A., Abdel-Fatah, T., Chan, S. Y., Chiang, P. W., Mongan, N. P., Rakha, E. A., Tomkinson, A. E., & Madhusudan, S. (2021). Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers. Theranostics, 11(17), 8350-8361. https://doi.org/10.7150/thno.51456

• Journal Article Type: Article
• Acceptance Date: Jun 10, 2021
• Online Publication Date: Jul 25, 2021
• Publication Date: Jul 25, 2021
• Deposit Date: Jul 27, 2021
• Publicly Available Date: Jul 27, 2021
• Journal: Theranostics
• Electronic ISSN: 1838-7640
• Publisher: Ivyspring International Publisher
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 17
• Pages: 8350-8361
• DOI: https://doi.org/10.7150/thno.51456
• Public URL: https://nottingham-repository.worktribe.com/output/5834869
• Publisher URL: https://www.thno.org/v11p8350.htm