Exploiting the Vulnerability of ARID1A Deficient Ovarian Cancers for Therapeutic Potential
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Embargo End Date
2026-09-26
ICR Authors
Authors
Amin, N
Document Type
Thesis or Dissertation
Date
2024-09-26
Date Accepted
Abstract
The switching defective/sucrose non-fermenting (SWI/SNF) chromatin remodelling complex is important for the cellular response to replication stress. 20% of cancers harbour modifications in SWI/SNF complex subunits. ARID1A, a key component of the SWI/SNF complex, is mutated across a variety of cancers, and notably in 35-57% of ovarian clear cell carcinomas (OCCC). Clinically applicable targeted therapies for this aggressive, chemo-resistant disease remains an unmet need. G-quadruplexes (G4s) are thermodynamically stable secondary DNA structures which are a consequence of folding of guanine-rich DNA sequences. Treatment with G4 stabilising ligands, some of which have entered clinical trials, leads to DNA double strand breaks (DSBs). This represents a therapeutic vulnerability for cancers with defects in the response to G4 ligands and resulting DNA DSBs. Here, isogenic cell line models were generated using CRISPR-Cas9 gene editing and genetic complementation of ARID1A to study the potential contribution of ARID1A to genotoxic stress. We found that ARID1A deficient cells show selective sensitivity to G4 stabilising ligands, and that there is evidence of delayed repair of DNA damage when ARID1A is deficient. Mechanistically, we discovered that NHEJ factors fail to mobilise onto chromatin after treatment with stabilising ligand PDS when ARID1A is deficient. Furthermore, we showed that inhibitor of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a protein ensuring effective NHEJ functions, when combined with PDS leads to synergistic decrease in cell viability in ARID1A deficient cells. These data provide new insights into G4 ligands-induced DNA damage and their repair in ARID1A-defective models. This knowledge could be exploited for a new therapeutic approach to treat ARID1A deficient ovarian cancer.
Citation
2024
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Genome Stability