Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy.
Mutat Res. 2020 May-Dec;821:111692. doi: 10.1016/j.mrfmmm.2020.111692. Epub 2020 Feb 25.
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.
DNA 依赖性蛋白激酶（DNA-PK）参与许多细胞途径。它在细胞对 DNA 损伤的反应、修复 DNA 双链断裂（DNA-DSBs）中起关键作用，因此在维持基因组完整性方面起着重要作用。此外，已表明 DNA-PK 可调节转录、参与免疫系统的发育并保护端粒。这些多效性的参与以及其在癌症中的表达失调使得 DNA-PK 成为癌症治疗中一个有趣的治疗靶点，尤其是与引起 DNA-DSB 的药物（如拓扑异构酶 II 抑制剂和电离辐射）联合使用时。最近已经合成了不同的 DNA-PK 小分子抑制剂，其中一些正在临床试验中进行测试。这篇综述讨论了已知的 DNA-PK 及其在肿瘤生物学、DNA 修复和癌症治疗中的作用，并批判性地讨论了其抑制作为一种潜在的治疗方法。
