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Griffin, Michaela (2019) Combatting chemoresistance: an analysis of DNA repair proteins ERCC1 and XPF and their chemotherapeutic implications in ovarian cancer. MRes thesis, University of Nottingham.

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Abstract

Platinum-based drugs form a key aspect of multimodal treatment to various cancers. Despite this, resistance to platinum therapy is a colossal threat encircling the treatment of ovarian cancers. It is well documented that an upregulation in DNA repair pathways is an advantageous characteristic for cancer cells and results in the emergence of chemoresistance. Nucleotide excision repair (NER) is essential in the DNA damage response (DDR) and removes bulky DNA adducts caused primarily by UV light. This pathway utilises Xeroderma Pigmentosum F (XPF) and Excision Repair Cross-Complementation Group 1 (ERCC1) endonucleases in the final cleavage of the 5’ DNA lesion. An intact nucleotide excision repair (NER) pathway is required for the correction of platinum-induced crosslinks; cells lacking functional NER show exquisite sensitivity to platinum agents.

A targeted study of both ERCC1 and XPF was carried out to determine their significance in association with chemoresistance and synthetic lethality in ovarian cancer. Preclinical analysis by the siRNA depletion of ERCC1 and XPF were tested against platinum sensitivity and inhibition by PARPi in a panel of platinum sensitive and platinum resistant ovarian cancer cell lines (A2780 and A2780cis). Furthermore, the clinical significance and clinicopathological correlations of ERCC1 and XPF was established in a cohort of 334 ovarian tumours.

Functional analysis revealed that ERCC1 knockdown increased platinum sensitivity activating apoptosis, inducing S phase arrest and resulting in higher double strand breaks (DSBs). PARP inhibition of ERCC1 and XPF depleted A2780cis cells show increased levels of DSBs, and a G2/M arrest. Clinicopathological analysis revealed increased ERCC1 nuclear expression was linked with poor progression free survival (p=0.048), higher histological grade (p=0.047) and higher histological stage (p=0.049). No significance data was seen between XPF and prognostic factors upon clinicopathological analysis. ERCC1 was shown to be an independently associated prognostic indicator for ovarian cancer, with high ERCC1 expression significantly correlating to poor progression free survival and overall survival.

Data from this study allows us to conclude that ERCC1 is a key predictor of platinum resistance in a large clinical cohort of ovarian cancers. Pre-clinically, ERCC1 or XPF depletion not only increased cisplatin sensitivity but also increased cytotoxicity to Olaparib (PARP1 inhibitor) therapy. Together, the data suggests that ERCC1 deficiency is not only a predictor of platinum sensitivity but may also be utilized to personalise Olaparib therapy in ovarian cancer patients.

Item Type:	Thesis (University of Nottingham only) (MRes)
Supervisors:	Srinivasan, Madhusudan Rahka, Emad
Keywords:	Chemoresistance, Olaparib, Cisplatin, ERCC1, XPF, DNA Repair, Nucleotide Excision Repair, Ovarian Cancer, Cancer treatment, Chemotherapy
Subjects:	QS-QZ Preclinical sciences (NLM Classification) > QZ Pathology
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	55788
Depositing User:	Griffin, Michaela
Date Deposited:	19 Jul 2019 04:40
Last Modified:	07 May 2020 11:47
URI:	https://eprints.nottingham.ac.uk/id/eprint/55788

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