title: Checkpoint kinase 1 expression is an adverse prognostic marker and therapeutic target in MYC-driven medulloblastoma.
abstract: Checkpoint kinase 1 (CHK1) is an integral component of the cell cycle as well as the DNA Damage Response (DDR) pathway. Previous work has demonstrated the effectiveness of inhibiting CHK1 with small-molecule inhibitors, but the role of CHK1 mediated DDR in medulloblastoma is unknown. CHK1, both at the mRNA and protein level, is highly expressed in medulloblastoma and elevated CHK1 expression in Group3 medulloblastoma is an adverse prognostic marker. CHK1 inhibition with the small-molecule drug AZD7762, results in decreased cell growth, increased DNA damage and cell apoptosis. Furthermore, AZD7762 acts in synergy with cisplatin in reducing cell proliferation in medulloblastoma. Similar phenotypic changes were observed with another CHK1 inhibitor, PF477736, as well as genetic knockdown using siRNA against CHK1. Treatments with small-molecule inhibitors of CHK1 profoundly modulated the expression of both upstream and downstream target proteins within the CHK1 signaling pathways. This suggests the presence of a feedback loop in activating CHK1. Overall, our results demonstrate that small-molecule inhibition of CHK1 in combination with, cisplatin, is more advantageous than either treatment alone, especially for Group 3 medulloblastoma, and therefore this combined therapeutic approach serves as an avenue for further investigation.
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Prince
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Ilango
authors.initials: I
authors.lastname: Balakrishnan
authors.affiliation: University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Monil
authors.initials: M
authors.lastname: Shah
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Mulcahy Levy
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Griesinger
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Irina
authors.initials: I
authors.lastname: Alimova
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Harris
authors.affiliation: Division of Pediatric Neurosurgery, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Birks
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Donson
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: Davidson
authors.affiliation: DKFZ German Cancer Research Center, University Hospital Düsseldorf, Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Division of Pediatric Neurosurgery, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Handler
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.|University of Colorado School of Medicine, Aurora, CO, United States.|Division of Pediatric Neurosurgery, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.|University of Colorado School of Medicine, Aurora, CO, United States.|Division of Pediatric Neurosurgery, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001570:Benzodiazepinones / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D000071877:Checkpoint Kinase 1 / Q000096:biosynthesis*; D002945:Cisplatin / Q000494:pharmacology; D018572:Disease-Free Survival; D016259:Genes, myc; D006801:Humans; D053208:Kaplan-Meier Estimate; D008527:Medulloblastoma / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D011720:Pyrazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D001570:Benzodiazepinones; D014408:Biomarkers, Tumor; C532366:PF 00477736; D011720:Pyrazoles; D013876:Thiophenes; D014508:Urea; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D002945:Cisplatin
keywords: CHK1; Myc; medulloblastoma