Targeting DNA-PK in cancer.

DNA-dependent protein kinase (DNA-PK) is involved in many cellular pathways. It has a key role in the cellular response to DNA damage, in the repair of DNA double-strand break (DNA-DSBs) and as a consequence an important role in maintaining genomic integrity. In addition, DNA-PK has been shown to modulate transcription, to be involved in the development of the immune system and to protect telomeres. These pleotropic involvements and the fact that its expression is de-regulated in cancer have made DNA-PK an intriguing therapeutic target in cancer therapy, especially when combined with agents causing DNA-DSBs such as topoisomerase II inhibitors and ionizing radiation. Different small molecule inhibitors of DNA-PK have been recently synthesized and some are now being tested in clinical trials. This review discusses what is known about DNA-PK, its role in tumor biology, DNA repair and cancer therapy and critically discusses its inhibition as a potential therapeutic approach.