{"doi":"10.1101/2020.05.23.111658","title":"Polymerase Theta Inhibition Kills Homologous Recombination Deficient Tumors","abstract":"Abstract PARP inhibitors (PARPi) have become a new line of therapy for Homologous Recombination (HR)-deficient cancers. However, resistance to PARPi has emerged as a major clinical problem. DNA polymerase theta (POLθ) is synthetic lethal with HR and a druggable target in HR-deficient cancers. Here, we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo . NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity, and phenocopies POLθ depletion. BRCA-deficient tumor cells and those with acquired PARPi resistance are sensitive to NVB in vitro and in vivo . Increased POLθ expression levels predict NVB sensitivity. The mechanism of NVB-mediated cell death in PARPi resistant cells is the accumulation of toxic RAD51 foci, which also provides a pharmacodynamic biomarker for NVB response. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance. One Sentence Summary We identified Novobiocin as a specific POLθ inhibitor that selectively kills naïve and PARPi resistance HR-deficient tumors in vitro and in vivo.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":119619,"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":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":556502,"name":"Camille Gelot","orcid":null,"position":1,"is_corresponding":false},{"id":555440,"name":"Constantia Pantelidou","orcid":"0000-0003-2750-9352","position":2,"is_corresponding":false},{"id":555441,"name":"Adam Y. Li","orcid":"0000-0001-7654-1469","position":3,"is_corresponding":false},{"id":556503,"name":"Hatice Yücel","orcid":null,"position":4,"is_corresponding":false},{"id":555442,"name":"Rachel E. Davis","orcid":"0000-0003-0359-381X","position":5,"is_corresponding":false},{"id":241555,"name":"Anniina Färkkilä","orcid":"0000-0002-3558-6617","position":6,"is_corresponding":false},{"id":256294,"name":"Bose Kochupurakkal","orcid":"0000-0001-8929-3070","position":7,"is_corresponding":false},{"id":555443,"name":"Aleem Syed","orcid":"0000-0001-7942-3900","position":8,"is_corresponding":false},{"id":230281,"name":"Geoffrey I. Shapiro","orcid":"0000-0002-3331-4095","position":9,"is_corresponding":false},{"id":107262,"name":"John A. Tainer","orcid":"0000-0003-1659-2429","position":10,"is_corresponding":false},{"id":288121,"name":"Brian S. J. Blagg","orcid":"0000-0002-6200-3480","position":11,"is_corresponding":false},{"id":555444,"name":"Raphaël Ceccaldi","orcid":"0000-0003-3049-4278","position":12,"is_corresponding":false},{"id":7163,"name":"Alan D. D’Andrea","orcid":"0000-0001-6168-6294","position":13,"is_corresponding":false},{"id":304103,"name":"Jia Zhou","orcid":"0000-0002-2156-0483","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:14:13.002105Z","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":[]}