Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice

• Published in: The Journal of clinical investigation 2016-11, Vol.126 (11), p.4076-4087
• Main Authors: Wei, Liang, Leibowitz, Brian J, Wang, Xinwei, Epperly, Michael, Greenberger, Joel, Zhang, Lin, Yu, Jian
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - immunology; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - immunology; Biomedical research; Cancer; Cell cycle; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Cycle - immunology; Cell division; Colleges & universities; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 4 - immunology; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - genetics; Cyclin-Dependent Kinase 6 - immunology; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - immunology; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; DNA Damage - immunology; DNA repair; Experiments; FDA approval; Gastrointestinal system; Gene expression; Intestinal Diseases - genetics; Intestinal Diseases - immunology; Intestinal Diseases - prevention & control; Kinases; Methods; Mice; Mice, Knockout; Phase transitions; Piperazines - pharmacology; Proteins; Pyridines - pharmacology; Radiation Injuries, Experimental - genetics; Radiation Injuries, Experimental - immunology; Radiation Injuries, Experimental - pathology; Radiation Injuries, Experimental - prevention & control; Radiotherapy; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - immunology; Rodents; Stem cells; Stem Cells - immunology; Stem Cells - pathology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - immunology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - immunology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI88410

Radiotherapy causes dose-limiting toxicity and long-term complications in rapidly renewing tissues, including the gastrointestinal tract. Currently, there is no FDA-approved agent for the prevention or treatment of radiation-induced intestinal injury. In this study, we have shown that PD 0332991 (PD), an FDA-approved selective inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), prevents radiation-induced lethal intestinal injury in mice. Treating mice with PD or a structurally distinct CDK4/6 inhibitor prior to radiation blocked proliferation and crypt apoptosis and improved crypt regeneration. PD treatment also enhanced LGR5+ stem cell survival and regeneration after radiation. PD was an on-target inhibitor of RB phosphorylation and blocked G1/S transition in the intestinal crypts. PD treatment strongly but reversibly inhibited radiation-induced p53 activation, which blocked p53-upregulated modulator of apoptosis-dependent (PUMA-dependent) apoptosis without affecting p21-dependent suppression of DNA damage accumulation, with a repair bias toward nonhomologous end joining. Further, deletion of PUMA synergized with PD treatment for even greater intestinal radioprotection. Our results demonstrate that the cell cycle critically regulates the DNA damage response and survival of intestinal stem cells and support the concept that pharmacological quiescence is a potentially highly effective and selective strategy for intestinal radioprotection.