{"doi":"10.3390/ijms23158412","title":"PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them","abstract":"<jats:p>PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40–70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage.</jats:p>","journal":"International Journal of Molecular Sciences","year":2022,"id":654990,"datarank":0.7130385286659547,"base_score":4.7535901911063645,"endowment":4.7535901911063645,"self_citation_contribution":0.7130385286659547,"citation_network_contribution":0.0,"self_endowment_contribution":0.7130385286659547,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":115,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1709564,"name":"Hye Jin Nam","orcid":"0000-0002-7121-3703","position":1,"is_corresponding":false},{"id":1709563,"name":"Dongha Kim","orcid":"0000-0002-3454-6605","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them","abstract":"<jats:p>PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40–70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage.</jats:p>","is_dataset_classified":null,"base_score":4.7535901911063645,"endowment":4.7535901911063645,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35955544","pmcid":"PMC9369301","openalex_id":"https://openalex.org/W4289134371","authors":[],"funders":[{"funder_name":"Ministry of Science and ICT","grant_id":"2020M3A9I4036072","title":null},{"funder_name":"Ministry of Science and ICT","grant_id":"2022R1A2C4002022","title":null},{"funder_name":"Ministry of Science and ICT","grant_id":"2021R1A4A3031875","title":null},{"funder_name":"Catholic Medical Center Research Foundation","grant_id":"the program year of 2021","title":null}],"total_grants":4,"fwci":9.4804,"citation_percentile":0.9880364,"influential_citations":0,"citation_trend":[{"year":2022,"count":2},{"year":2023,"count":17},{"year":2024,"count":43},{"year":2025,"count":40},{"year":2026,"count":13}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/23/15/8412/pdf?version=1659343806","host_type":"journal"},{"url":"https://www.mdpi.com/1422-0067/23/15/8412/pdf?version=1659343806","host_type":"publisher"},{"url":"https://www.mdpi.com/1422-0067/23/15/8412/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/ijms23158412","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35955544","host_type":"repository"},{"url":"https://doaj.org/article/5511ae5012064d3ca030cdd11fd4485e","host_type":"repository"},{"url":"https://dx.doi.org/10.3390/ijms23158412","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9369301","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9369301","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9369301?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["PARP inhibition in cancer therapy","DNA Repair Mechanisms","CRISPR and Genetic Engineering"],"mesh_terms":["Poly(ADP-ribose) Polymerase Inhibitors","Synthetic Lethal Mutations","Antineoplastic Agents","Female","Humans","Mutation","Ovarian Neoplasms"],"keywords":["Synthetic lethality","Poly ADP ribose polymerase","PARP inhibitor","Medicine","Bioinformatics","Cancer research","Pharmacology","Biology","DNA repair","Gene","Genetics","Polymerase","Parp1","Homologous Recombination (Hr)","Protac","Hydrophobic Tagging","Resistance To Parp Inhibitor"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"},{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T09:12:49.580445Z","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":[]}