Enhancing radiotherapy through a greater understanding of homologous recombination

Abstract

Radiotherapy for the treatment of cancer can cause a wide range of cellular effects, the most biologically potent of which is the double-strand break in DNA. The process of repairing DNA double-strand breaks involves 1 of 2 major mechanisms: nonhomologous end joining or homologous recombination. In this review, we review the molecular mechanisms of homologous recombination, in particular as it relates to the repair of DNA damage from ionizing radiation. We also present specific situations in which homologous recombination may be dysfunctional in human cancers and how this functional abnormality can be recognized. We also discuss the therapeutic opportunities that can be exploited based on deficiencies in homologous recombination at various steps in the DNA repair pathway. Side-by-side with these potential therapeutic opportunities, we review the contemporary clinical trials in which strategies to exploit these defects in homologous recombination can be enhanced by the use of radiotherapy in conjunction with biologically targeted agents. We conclude that the field of radiation oncology has only scratched the surface of a potentially highly efficacious therapeutic strategy.