title: Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy.
abstract: Disabling mutations in genome maintenance and DNA repair pathways are frequently observed in cancer. These DNA repair defects represent genetic aberrations that are specific to cancer cells and not present in healthy tissues. It is thought that these molecular defects produce a "mutator phenotype," which allows incipient cancer cells to accumulate additional cancer-promoting mutations. In recent years, our molecular understanding of DNA double-strand break (DSB) repair mechanisms has led to the development of targeted therapeutic approaches to selectively eradicate cancer cells that display defects in homologous recombination-mediated DNA DSB repair. These regimens for the treatment of homologous recombination-defective tumors predominantly aim at pharmacologically repressing the activity of PARP1, which is crucial for base excision repair, or to inhibit the nonhomologous end joining kinase DNA-PKcs (DNA-dependent protein kinase, catalytic subunit). Normal tissue can bypass PARP1- or DNA-PKcs inhibitor-induced genotoxic lesions via homologous recombination-mediated DNA DSB repair. In contrast, homologous recombination-defective cancer cells are unable to properly repair DNA DSBs, in the presence of PARP1 or DNA-PKcs inhibitors, ultimately leading to apoptotic cancer cell death.
authors.affiliation: Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany. Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany. christian.reinhardt@uk-koeln.de fdietlei@smail.uni-koeln.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Dietlein
authors.affiliation: Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany. Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany. christian.reinhardt@uk-koeln.de fdietlei@smail.uni-koeln.de.
authors.forename: H Christian
authors.initials: HC
authors.lastname: Reinhardt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents