Understanding the basics for translating the base excision repair pathway from benchtop to bedside in cancer treatment

This chapter will focus on the base excision repair (BER) pathway, which is responsible for the repair of single-base lesions. BER is the predominant pathway for the repair of oxidative and alkylation DNA damage, as well as baseless sites. Data from several studies indicate that the coordination of the steps within this pathway is essential to genomic integrity and completion of repair. Without this balance of enzymatic activities, incomplete processing of the damage occurs, repair intermediates accumulate, and eventually cells die. Inhibition of proliferation and cell death are desirable in tumor therapy, therefore inhibitors of BER proteins are under development and are currently being evaluated in the clinic, particularly in combination with numerous existing chemotherapeutic agents and radiation therapy. Combination therapy with agents that generate DNA damage that is repaired through BER seems promising. Both preclinical and early clinical trials demonstrate the efficacy of this hypothesis. Inhibitors of BER proteins (ie, APE1 and PARP1) have indications as single agents in tumor with a reduced capacity for DNA repair (BRCA1/2 mutations) and in combination regimens. BER inhibitors will likely increase the therapeutic index of currently used agents and will play a role in secondary treatments upon acquisition of resistance to traditional therapies.This chapter will give an overview of the BER pathway, with emphasis on the coordination of this complex DNA repair system with a glimpse on the current knowledge of the noncanonical roles of BER proteins. The current involvement of BER enzymes in tumorigenesis and therapy resistance, as well as the possibility to target BER enzymes for anticancer therapy, will be described at the end of this section.