Pharmacological methods to transcriptionally modulate double-strand break DNA repair

Abstract

There is much interest in targeting DNA repair pathways for use in cancer therapy, as the effectiveness of many therapeutic agents relies on their ability to cause damage to DNA, and deficiencies in DSB repair pathways can make cells more sensitive to specific cancer therapies. For example, defects in the double-strand break (DSB) pathways, non-homologous end joining (NHEJ) and homology-directed repair (HDR), induce sensitivity to radiation therapy and poly(ADP)-ribose polymerase (PARP) inhibitors, respectively. However, traditional approaches to inhibit DNA repair through small molecule inhibitors have often been limited by toxicity and poor bioavailability. This review identifies several pharmacologic manipulations that modulate DSB repair by reducing expression of DNA repair factors. A number of pathways have been identified that modulate activity of NHEJ and HDR through this mechanism, including growth and hormonal receptor signaling pathways as well as epigenetic modifiers. We also discuss the effects of anti-angiogenic therapy on DSB repair. Preclinically, these pharmacological manipulations of DNA repair factor expression have been shown to increase sensitivity to specific cancer therapies, including ionizing radiation and PARP inhibitors. When applicable, relevant clinical trials are discussed and areas for future study are identified.

Keywords: Double-strand break DNA repair; Homology-directed repair; Non-homologous end joining; PARP inhibitors; Radiation therapy; Synthetic lethality.