title: Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition.
abstract: Total body irradiation (TBI) can induce lethal myelosuppression, due to the sensitivity of proliferating hematopoietic stem/progenitor cells (HSPCs) to ionizing radiation (IR). No effective therapy exists to mitigate the hematologic toxicities of TBI. Here, using selective and structurally distinct small molecule inhibitors of cyclin-dependent kinase 4 (CDK4) and CDK6, we have demonstrated that selective cellular quiescence increases radioresistance of human cell lines in vitro and mice in vivo. Cell lines dependent on CDK4/6 were resistant to IR and other DNA-damaging agents when treated with CDK4/6 inhibitors. In contrast, CDK4/6 inhibitors did not protect cell lines that proliferated independently of CDK4/6 activity. Treatment of wild-type mice with CDK4/6 inhibitors induced reversible pharmacological quiescence (PQ) of early HSPCs but not most other cycling cells in the bone marrow or other tissues. Selective PQ of HSPCs decreased the hematopoietic toxicity of TBI, even when the CDK4/6 inhibitor was administered several hours after TBI. Moreover, PQ at the time of administration of therapeutic IR to mice harboring autochthonous cancers reduced treatment toxicity without compromising the therapeutic tumor response. These results demonstrate an effective method to mitigate the hematopoietic toxicity of IR in mammals, which may be potentially useful after radiological disaster or as an adjuvant to anticancer therapy.
authors.affiliation: Department of Genetics, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Søren M
authors.initials: SM
authors.lastname: Johnson
authors.forename: Chad D
authors.initials: CD
authors.lastname: Torrice
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Bell
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Monahan
authors.forename: Qi
authors.initials: Q
authors.lastname: Jiang
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ramsey
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011827:Radiation
chemical_list: D000970:Antineoplastic Agents; D050763:Cyclin-Dependent Kinase Inhibitor p18; D051358:Cyclin-Dependent Kinase 4