Molecular Pathways Molecular Pathways: Exploiting Tumor-Specific Molecular Defects in DNA Repair Pathways for Precision Cancer Therapy

Disablingmutations in genomemaintenance andDNA 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 ofDNAdouble-strand break (DSB) repairmechanisms 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 PARP1or 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. Clin Cancer Res; 20(23); 5882–7. 2014 AACR. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. Editor's Disclosures The following editor(s) reported relevant financial relationships: P.S. Steeg reports receiving commercial research grants from Geron, GlaxoSmithKline, and Sanofi. CME Staff Planners' Disclosures The members of the planning committee have no real or apparent conflicts of interest to disclose.