Lack of DNA repair mechanisms in solid tumours. Therapeutic options and diagnostic challenges – focus on homologous recombination

Therapeutic approaches based on the principle of synthetic lethality with DNA repair aberrations offer an effective strategy for cancer treatment, since DNA repair pathway aberrations are common in tumor cells but are largely absent in normal cells. Therefore, agents that target DNA repair deficient cells, such as PARP inhibitors targeting homologous recombination (HR) deficiency, have a clinically exploitable therapeutic window. Here we are reviewing the theoretical principle of synthetic lethality-based targeting of DNA repair deficiencies with a special emphasis on homologous recombination deficiency. We will present the palette of currently approved PARP inhibitors and the various companion diagnostics currently in use to prioritize patients for this form of therapy. We will discuss the various mechanisms leading to PARP inhibitor resistance and how it can be overcome by a variety of therapeutic strategies. We will specifically discuss the possible use of PARP inhibitors in solid tumor types rarely associated with BRCA1/2 mutations. Finally, we will briefly review other DNA repair deficiencies that are currently investigated for therapeutic intervention.