Abstract ES2-1: DNA Repair Pathways and Tumorigenesis

Abstract

Abstract The genome is constantly undergoing DNA damage from endogenous and environmental sources. DNA damage response pathways detect and repair DNA damage and signal to cell cycle checkpoints to allow repair to take place, thus promoting genomic stability. Multiple DNA repair pathways exist: single-strand damage or base errors are repaired by base excision repair, nucleotide excision repair or mismatch repair, while DNA doublestrand breaks are repaired by nonhomologous end joining or homologous recombination repair. These pathways may be used to repair damage caused by anticancer chemotherapy and radiotherapy. Some defects in DNA damage responses are associated with the genomic instability that is a characteristic of cancer. Targeting the remaining DNA damage response pathways could potentially result in tumor selective therapies. Poly(ADP-ribose) polymerase (PARP) inhibitors have shown great promise in this respect, and early clinical data are beginning to emerge. PARP inhibitors enhance the activity of several DNA damaging and crosslinking chemotherapeutic agents and ionizing radiation. An exciting aspect is the selective toxicity of PARP inhibitors in DNA defective tumors, such as those associated with BRCA mutations or breast cancers exhibiting the triple-negative phenotype. This discovery has led to a paradigm shift in cancer therapy representing a targeted, tumor-specific, nontoxic therapy that is supported by emerging clinical data. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES2-1.