{"doi":"10.1101/2021.03.03.433791","title":"LCK Regulates Homologous Recombination DNA Repair Identifying a New Target for Sensitizing PARP Inhibitors in HR Proficient Ovarian Cancer","abstract":"Abstract Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success in treatment of HR repair deficient cancers has not translated to HR-proficient cancer. Our studies identify the mechanism of non-receptor lymphocyte-specific protein tyrosine kinase (LCK) in HR repair in endometrioid epithelial ovarian cancer (eEOC). LCK expression is induced and activation in the nucleus in response to DNA damage insult. LCK inhibition attenuates expression of RAD51, BRCA1, and BRCA2 proteins necessary for HR-mediated DNA repair, sufficient to suppress RAD51 foci formation, and augments γH2AX foci formation. Mechanistically, DNA damage leads to direct interaction of LCK with RAD51 and BRCA1 in a kinase dependent manner. Attenuation of LCK sensitized HR-proficient eEOC cells to PARP inhibitor in cell culture and pre-clinical mouse studies. These findings identify a new mechanism for expanding utility of PARP inhibitors in HR proficient ovarian cancer. Graphical Abstract","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223477,"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":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":824934,"name":"Rashmi Bharti","orcid":"0000-0002-7612-7695","position":1,"is_corresponding":false},{"id":570708,"name":"Chad Braley","orcid":"0000-0002-0629-3508","position":2,"is_corresponding":false},{"id":468653,"name":"Ravi Kumar Alluri","orcid":null,"position":3,"is_corresponding":false},{"id":571724,"name":"Emily Esakov","orcid":null,"position":4,"is_corresponding":false},{"id":824935,"name":"Katie Crean-Tate","orcid":"0000-0003-2690-9063","position":5,"is_corresponding":false},{"id":256164,"name":"Keith R. McCrae","orcid":"0000-0001-7340-475X","position":6,"is_corresponding":false},{"id":570281,"name":"Amy Joehlin‐Price","orcid":"0000-0002-1608-4785","position":7,"is_corresponding":false},{"id":570711,"name":"Peter G. Rose","orcid":"0000-0003-2676-0166","position":8,"is_corresponding":false},{"id":240691,"name":"Justin D. Lathia","orcid":"0000-0003-3168-7290","position":9,"is_corresponding":false},{"id":367228,"name":"Zihua Gong","orcid":"0000-0002-8008-0615","position":10,"is_corresponding":false},{"id":367227,"name":"Ofer Reizes","orcid":"0000-0003-0075-6871","position":11,"is_corresponding":false},{"id":821335,"name":"Goutam Dey","orcid":"0000-0002-8210-3219","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-18T23:54:11.061295Z","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":[]}