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 involve-ments 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.