{"doi":"10.1101/2025.04.09.647957","title":"Chemical inhibition of RPA gap protection sensitizes BRCA1-deficient cancers to PARP inhibition","abstract":"Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) are standard of care for many BRCA1 deficient cancers, though few cures are achieved. We sought to determine if targeting the protection of the single-strand DNA gaps induced by PARPi in BRCA-deficient cancers could increase efficacy. Replication protein A (RPA) participates in critical protein-protein and protein-DNA interactions to protect single-stranded DNA (ssDNA) and support DNA metabolism. We have reported the optimization of small molecule RPA inhibitors (RPAi) that target protein-ssDNA interactions to chemically exhaust RPA and elicit single-agent anticancer activity. RPAi sensitizes cells to PARPi in BRCA1-deficient non-cancerous cells, where ssDNA gap formation drives therapeutic efficacy. We show that RPAi treatment abolishes PARPi-induced replication gap protection, resulting in genomic instability via replication fork degradation and chromosomal integrity, and that, in vivo , the RPA and PARP targeted combination abrogates cancer growth in a BRCA1-mutant breast cancer model. We find that genetic predispositions to ssDNA gap accumulation correlate with RPAi sensitivity, and BRCA1-proficient cells remain sensitive to combination treatment but require more PARP inhibition to increase ssDNA gaps. RPAi-PARPi combination activity in patient-derived ovarian cancer models demonstrates the utility of targeting gap protection to increase PARPi sensitivity and circumvent resistance. Collectively, this work provides a unifying mechanism of chemical RPA exhaustion as a cancer therapeutic strategy. One Sentence Summary Inhibition of single-strand DNA gap protection potentiates PARP targeted treatment of BRCA1 deficient cancers.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":564287,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":669652,"name":"Matthew R. Jordan","orcid":"0000-0003-0095-8078","position":1,"is_corresponding":false},{"id":335359,"name":"Joy Garrett","orcid":null,"position":2,"is_corresponding":false},{"id":326016,"name":"Karen E. Pollok","orcid":"0000-0001-6031-5707","position":3,"is_corresponding":false},{"id":1467685,"name":"Hilary D. Hinshaw","orcid":null,"position":4,"is_corresponding":false},{"id":1467686,"name":"Xierzhatijiang Sulaiman","orcid":null,"position":5,"is_corresponding":false},{"id":810402,"name":"Sheng Liu","orcid":"0000-0003-2731-9591","position":6,"is_corresponding":false},{"id":300846,"name":"Jun Wan","orcid":"0000-0001-9286-6562","position":7,"is_corresponding":false},{"id":333351,"name":"Katherine S. Pawelczak","orcid":"0000-0002-2099-2858","position":8,"is_corresponding":false},{"id":333355,"name":"John J. Turchi","orcid":"0000-0001-5375-2992","position":9,"is_corresponding":false},{"id":335353,"name":"Pamela S. VanderVere-Carozza","orcid":null,"position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:20.933088Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}