{"doi":"10.1101/2024.07.10.602941","title":"Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer","abstract":"Abstract In advanced castration resistant prostate cancer (CRPC), mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated ( ATM ) are common. While poly(ADP-ribose) polymerase inhibitors are approved in this context, their clinical efficacy remains limited. Thus, there is a compelling need to identify alternative therapeutic avenues for ATM mutant prostate cancer patients. Here, we generated matched ATM-proficient and ATM-deficient CRPC lines to elucidate the impact of ATM loss on DDR in response to DNA damage via irradiation. Through unbiased phosphoproteomic screening, we unveiled that ATM-deficient CRPC lines maintain dependence on downstream ATM targets through activation of ATR and DNA-PKcs kinases. Dual inhibition of ATR and DNA-PKcs effectively inhibited downstream γH2AX foci formation in response to irradiation and radiosensitized ATM-deficient lines to a greater extent than either ATM-proficient controls or single drug treatment. Further, dual inhibition abrogated residual downstream ATM pathway signaling and impaired replication fork dynamics. To circumvent potential toxicity, we leveraged the RUVBL1/2 ATPase inhibitor Compound B, which leads to the degradation of both ATR and DNA-PKcs kinases. Compound B effectively radiosensitized ATM-deficient CRPC in vitro and in vivo , and impacted replication fork dynamics. Overall, dual targeting of both ATR and DNA-PKcs is necessary to block DDR in ATM-deficient CRPC, and Compound B could be utilized as a novel therapy in combination with irradiation in these patients. Graphical Abstract","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":491378,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9358,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1337345,"name":"Andrea Woods","orcid":null,"position":1,"is_corresponding":false},{"id":874808,"name":"Karla Parra","orcid":"0000-0002-2408-6860","position":2,"is_corresponding":false},{"id":351736,"name":"Zoi E. Sychev","orcid":"0000-0002-9830-5245","position":3,"is_corresponding":false},{"id":986567,"name":"Alice Mazzagatti","orcid":"0000-0003-1627-0446","position":4,"is_corresponding":false},{"id":385822,"name":"Lan Yu","orcid":"0000-0002-7087-0883","position":5,"is_corresponding":false},{"id":385820,"name":"Collin Gilbreath","orcid":"0000-0002-8683-983X","position":6,"is_corresponding":false},{"id":227583,"name":"Peter Ly","orcid":"0000-0001-8946-7069","position":7,"is_corresponding":false},{"id":351743,"name":"Justin M. Drake","orcid":"0000-0002-8329-7748","position":8,"is_corresponding":false},{"id":385824,"name":"Ralf Kittler","orcid":"0000-0002-0098-6792","position":9,"is_corresponding":false},{"id":250656,"name":"Mia Hofstad","orcid":"0000-0001-5530-7817","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:45.247225Z","pmid":"39026771","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":[]}