Investigating MAT2A inhibition in ovarian high-grade serous carcinoma (HGSC)
File(s)
Author(s)
Bray, Chandler
Type
Thesis
Abstract
Since 2014, the use of PARP inhibitors (PARPi) has produced a substantial clinical benefit in patients with BRCA1/2-mutated or homologous recombination deficient (HRD) HGSC. However, PARPi resistance is frequent, subsequently leading to disease relapse and potential mortality. To take advantage of other common cancer mutations, I have investigated methylthioadenosine phosphorylase (MTAP)-deletion in HGSC. Approximately 15% of cancers have a homozygous deletion in the tumour suppressor gene CDKN2A frequently associated with passenger deletion of the methionine salvage gene MTAP. An MTAP deletion and subsequent build-up of MTAP substrate (methylthioadenosine or MTA) has been shown to be synthetically lethal with the inhibition of MAT2A or PRMT5, due to subsequent deficiency in DNA damage repair capacity. Here, I broadly characterise the effect of MAT2A inhibition in MTAP-expressing and MTAP-deleted HGSC on the metabolome, the proteome, the lipidome, and the levels of DNA damage and cell death. In this thesis, I report a dramatic reprogramming in metabolic state and specific growth inhibition of MTAP-deleted HGSC cell in vitro when treated with a clinical MAT2A inhibitor (AG-270) due to the accumulation of MTA and reduced PRMT5 activity. However, in vivo I did not observe MTA accumulation in MTAP-deleted tumours which may limit drug response in patients. Furthermore, MAT2A inhibition causes changes in the oxidative stress response, and I observed hepatological and haematological toxicity especially in erythroid differentiation. The combination of AG-270 and a PARPi (Olaparib) shows a synergistic benefit, reducing human HGSC cell growth in vitro and resulting in a substantial increase in levels of DNA damage and apoptosis at lower drug doses than for the monotherapy. Furthermore, combination therapy may improve PARPi-sensitivity in HGSC and alleviate any toxic oxidative stress effects that are caused by efficacious dose in vivo by reducing MAT2Ai dosage.
Version
Open Access
Date Issued
2024-11-08
Date Awarded
2025-04-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Keun, Hector
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)