Ovarian clear cell carcinoma (OCCC) is an aggressive, chemoresistant subtype of epithelial ovarian cancer frequently characterised by loss-of-function mutations in ARID1A, a DNA-binding subunit of the SWI/SNF chromatin remodelling complex. ARID1A deficiency has been linked to impaired DNA damage responses and increased sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition, particularly following alkylation damage. PARP inhibitors exert cytotoxicity through catalytic inhibition of poly ADP-ribose (PAR) synthesis and through PARP-DNA complex stabilisation (PARP trapping). The relative contribution of these mechanisms in the context of ARID1A loss remains unclear.

Isogenic RMG1 OCCC cell lines were employed, either wild-type or with CRISPR-mediated ARID1A knockout. Cells were treated with the alkylating agent methyl methanesulfonate (MMS) in combination with equimolar concentrations of the PARP inhibitors veliparib (weak PARP trapper) or talazoparib (potent PARP trapper). Cell viability was assessed using an MTS assay, and proliferation was monitored by live-cell imaging. Inhibition of PARP catalytic activity was confirmed by Western blot detection of PAR polymers. All results were verified on at least two independent ARID1A knockout clones.

MMS sensitised ARID1A knockout cells to veliparib and talazoparib, highlighting the impact of DNA damage in the context of PARP inhibition. Strikingly, ARID1A knockout cells exhibited pronounced sensitivity to talazoparib even in the absence of MMS, revealing an intrinsic vulnerability to PARP trapping independent of exogenous alkylation. These findings suggest that ARID1A loss preferentially sensitises cells to PARP-DNA complex stabilisation over catalytic inhibition alone. Ongoing experiments aim to decipher the mechanism underlying the enhanced talazoparib sensitivity observed in ARID1A-deficient cells. We hypothesise that (i) ARID1A loss induces replication stress and impairs replication fork stability, thereby increasing susceptibility to PARP trapping, and (ii) ARID1A deficiency results in elevated endogenous base damage and/or defective base-damage processing, thereby increasing reliance on PARP-mediated repair. To investigate this, we have generated isogenic RMG1 parental and ARID1A-knockout cell lines with altered base excision repair initiation capacity. These models are currently being used to dissect the contribution of endogenous base damage to sensitivity to PARP trapping in ARID1A-deficient cells.

Our study demonstrates that ARID1A deficiency creates a selective sensitivity to PARP trapping, independent of exogenous DNA damage. This mechanistic link between SWI/SNF dysfunction and trapped PARP-DNA complexes suggest a promising therapeutic avenue for ARID1A-mutant OCCC, potentially guiding the rational use of PARP-trapping inhibitors in this challenging cancer subtype.