Oncotarget

Research Papers:

Checkpoint kinase 1 expression is an adverse prognostic marker and therapeutic target in MYC-driven medulloblastoma

Eric W. Prince, Ilango Balakrishnan, Monil Shah, Jean M. Mulcahy Levy, Andrea M. Griesinger, Irina Alimova, Peter S. Harris, Diane K. Birks, Andrew M. Donson, Nathan Davidson, Marc Remke, Michael D. Taylor, Michael H. Handler, Nicholas K. Foreman, Sujatha Venkataraman and Rajeev Vibhakar _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:53881-53894. https://doi.org/10.18632/oncotarget.10692

Metrics: PDF 1056 views  |   HTML 1808 views  |   ?  


Abstract

Eric W. Prince1,*, Ilango Balakrishnan1,*, Monil Shah2, Jean M. Mulcahy Levy1, Andrea M. Griesinger1, Irina Alimova1, Peter S. Harris1, Diane K. Birks3, Andrew M. Donson1, Nathan Davidson1, Marc Remke5, Michael D. Taylor4, Michael H. Handler3, Nicholas K. Foreman1,2,3, Sujatha Venkataraman1, Rajeev Vibhakar1,2,3

1Department 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

2University of Colorado School of Medicine, Aurora, CO, United States

3Division of Pediatric Neurosurgery, Children’s Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States

4Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada

5DKFZ German Cancer Research Center, University Hospital Düsseldorf, Heidelberg, Germany

*These authors have contributed equally to this work

Correspondence to:

Rajeev Vibhakar, email: Rajeev.vibhakar@ucdenver.edu

Keywords: medulloblastoma, CHK1, Myc

Received: June 05, 2015     Accepted: July 05, 2016     Published: July 19, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 10692