Chemical inhibition of DNA repair kinases as a promising tool in oncology

Abstract

Background: DNA repair pathways play a major role in tumour resistance towards chemo- and radiotherapy. Therefore, inhibitors of specific DNA repair pathways might be advantageous when used in combination with DNA-damaging agents, such as ionizing radiation. This review put particular emphasis on the key DNA repair enzymes: DNA-dependent protein kinase (DNA-PK), ataxia-telangiectasia mutated kinase (ATM) and ATM-Rad3-related kinase (ATR) and their specific inhibitors in the context of radio-sensitization. Results: We reviewed recent studies on novel and potent inhibitors and found evidence that inhibitors of DNA repair pathways such as small molecule inhibitors could be efficient and selective in tumour cells. Interpretation of recent literature results accompanied with implications for practice and further research are presented. Conclusions: The prospects of targeting DNA repair enzymes to treat cancer are optimistic, but future work will show if this approach has a significant in vivo efficacy, since we are still waiting for the inhibitor which would pass all phases in clinical trials. In spite of the fact that a number of drugs possess interesting synergy of radiotherapy in vitro, the future use will depend on developing compounds with improved solubility and the serum half-life. Normal tissue toxicity leading to a significant increase of radiotherapy efficiency remains a key question that might be answered only by clinical trials.

Keywords

• dna repair
• inhibitor
• dna-pk
• atm
• atr
• ionising radiation