{"doi":"10.1093/jnci/djx059","title":"Drugging the Cancers Addicted to DNA Repair","abstract":null,"journal":"JNCI: Journal of the National Cancer Institute","year":2017,"id":591062,"datarank":5.376567631975919,"base_score":5.10594547390058,"endowment":5.10594547390058,"self_citation_contribution":0.7658918210850871,"citation_network_contribution":4.610675810890832,"self_endowment_contribution":0.7658918210850871,"citer_contribution":4.610675810890832,"corpus_percentile":null,"corpus_rank":null,"citation_count":164,"citer_count":154,"citers_with_citation_signal":126,"citers_with_endowment":126,"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":1512203,"name":"Dennie Jones","orcid":null,"position":1,"is_corresponding":false},{"id":191539,"name":"Suk-Hee Lee","orcid":null,"position":2,"is_corresponding":false},{"id":420174,"name":"Elizabeth A. Williamson","orcid":"0000-0002-8751-7728","position":3,"is_corresponding":false},{"id":240060,"name":"Robert Hromas","orcid":"0000-0002-1916-6276","position":4,"is_corresponding":false},{"id":420176,"name":"Jac A. Nickoloff","orcid":"0000-0001-8606-7545","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Drugging the Cancers Addicted to DNA Repair","abstract":"Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.","is_dataset_classified":null,"base_score":5.10594547390058,"endowment":5.10594547390058,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"28521333","pmcid":"PMC5436301","openalex_id":"https://openalex.org/W2614456022","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"GM084020","title":null},{"funder_name":"National Institutes of Health","grant_id":"CA151367","title":null},{"funder_name":"National Institutes of Health","grant_id":"GM109645","title":null},{"funder_name":"National Institutes of Health","grant_id":"CA205224","title":null},{"funder_name":"NCI NIH HHS","grant_id":"F31 CA260794","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM109645","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA151367","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA205224","title":null},{"funder_name":"National Institutes of Health","grant_id":"1R01GM084020-01A1","title":"METNASE ROLES IN NHEJ, DNA INTEGRATION AND TRANSLOCATION"},{"funder_name":"National Institutes of Health","grant_id":"5R01CA151367-03","title":"Non-Homologous End Joining Repair in Humans"},{"funder_name":"National Institutes of Health","grant_id":"5R01GM109645-02","title":"Mechanisms for Chromosomal Translocations"}],"total_grants":11,"fwci":8.6968,"citation_percentile":0.98645504,"influential_citations":0,"citation_trend":[{"year":2016,"count":1},{"year":2017,"count":3},{"year":2018,"count":17},{"year":2019,"count":20},{"year":2020,"count":41},{"year":2021,"count":30},{"year":2022,"count":12},{"year":2023,"count":13},{"year":2024,"count":10},{"year":2025,"count":13},{"year":2026,"count":4}],"oa_status":"bronze","license":"CC BY NC","oa_locations":[{"url":"https://academic.oup.com/jnci/article-pdf/109/11/djx059/23698913/djx059.pdf","host_type":"journal"},{"url":"https://academic.oup.com/jnci/article-pdf/109/11/djx059/23698913/djx059.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/jnci/article-pdf/109/11/djx059/23698913/djx059.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/jnci/djx059","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/28521333","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5436301","host_type":"repository"},{"url":"https://hdl.handle.net/1805/13930","host_type":"repository"},{"url":"http://hdl.handle.net/1805/13930","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC5436301","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC5436301?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1093/jnci/djx059","host_type":""},{"url":"https://dx.doi.org/10.1093/jnci/djx059","host_type":""}],"fields_of_study":["PARP inhibition in cancer therapy","DNA Repair Mechanisms","BRCA gene mutations in cancer","0301 basic medicine","03 medical and health sciences"],"mesh_terms":["Poly(ADP-ribose) Polymerase Inhibitors","Synthetic Lethal Mutations","Antineoplastic Agents","DNA Repair","Humans","Neoplasms","Genes, BRCA1","Genes, BRCA2","DNA Mismatch Repair","Molecular Targeted Therapy","Homologous Recombination","DNA End-Joining Repair"],"keywords":["Synthetic lethality","DNA repair","Genome instability","Biology","DNA damage","PARP1","Cancer research","DNA","DNA mismatch repair","Mutation","Genetics","Poly ADP ribose polymerase","Gene","Polymerase","DNA End-Joining Repair","Synthetic lethal mutations","Genes, BRCA2","Genes, BRCA1","Antineoplastic Agents","Review","Poly(ADP-ribose) Polymerase Inhibitors","Neoplasms","Humans","Molecular targeted therapy","Homologous recombination","BRCA1","BRCA2","Genes"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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