Functional characterisation and target discovery in DNA damage response-altered endometrial cancer
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Embargo End Date
2025-10-29
ICR Authors
Authors
Zhou, J
Document Type
Thesis or Dissertation
Date
2025-04-29
Date Accepted
Abstract
DNA damage response (DDR) genes are frequently altered in cancer, which can lead to protein loss-of-function (LoF) and DDR defects that can be therapeutically targeted using synthetic lethality (SL). Endometrial cancer (EC), a gynaecologic malignancy with rising incidence and mortality and an urgent need for novel treatment options, is characterised by a high prevalence of DDR alterations. Here, two complementary approaches were used for SL target-biomarker discovery in EC. The first hypothesis-driven approach focused on alterations in the ataxia-telangiectasia mutated (ATM) DDR kinase, which is frequently mutated in EC, but the functional impact of most variants is unknown. It was hypothesised that ATM mutations in EC were LoF drivers that could be targeted using DDR inhibitors (DDRis). However, functional characterisation of ATM mutations in EC cells revealed no clear correlation between mutation status, protein expression, pathway activation, and sensitivity to DDRis. Although reduced or partially aberrant ATM function was observed in some ATM-mutant EC cells, ATM mutations retained kinase function and no targetable ATM deficiency was identified. In the second approach, The Institute of Cancer Research-developed Target/Biomarker/Lineage (TBL) bioinformatic pipeline was refined and optimised to identify novel SL targets specific to DDR LoF alterations in EC. Downstream refinement of significant hits, following pipeline SL analysis based on Cancer Dependency Map datasets, identified four target-biomarker gene pairs for experimental validation. Initial experiments in EC cell lines with altered or wild-type biomarker status provided positive evidence for TYMS/MSH2 and CAD/TRRAP, but were inconclusive for MECOM/SLX4 and ASH1L/SLX4. Taken together, these studies show the power of informatics approaches in discovering novel SL interactions, highlight the complexity of SL target-biomarker discovery in EC, and provide a starting point for novel SL target drug discovery for treatment of DDR-altered EC patients.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Target Eval & Mol Ther