Targeting homologous recombination-mediated DNA repair in cancer

DNA is the target of many traditional non-specific chemotherapeutic drugs. New drugs or therapeutic approaches with a more rational and targeted component are mandatory to improve the success of cancer therapy. The homologous recombination (HR) pathway is an attractive target for the development of inhibitors because cancer cells rely heavily on HR for repair of DNA double-strand breaks resulting from chemotherapeutic treatments. Additionally, the discovery that poly(ADP)ribose polymerase-1 inhibitors selectively kill cells with genetic defects in HR has spurned an even greater interest in inhibitors of HR.

HR drives the repair of broken DNA via numerous protein-mediated sequential DNA manipulations. Due to extensive number of steps and proteins involved, the HR pathway provides a rich pool of potential drug targets. This review discusses the latest developments concerning the strategies being explored to inhibit HR. Particular attention is given to the identification of small molecule inhibitors of key HR proteins, including the BRCA proteins and RAD51.

Current HR inhibitors are providing the basis for pharmaceutical development of more potent and specific inhibitors to be applied in mono- or combinatorial therapy regimes, while novel targets will be uncovered by experiments aimed to gain a deeper mechanistic understanding of HR and its subpathways.