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Oncotarget. 2016 Aug 16;7(33):53881-53894. doi: 10.18632/oncotarget.10692.

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

Author information

1
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.
2
University of Colorado School of Medicine, Aurora, CO, United States.
3
Division of Pediatric Neurosurgery, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
4
DKFZ German Cancer Research Center, University Hospital Düsseldorf, Heidelberg, Germany.
5
Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.

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.

KEYWORDS:

CHK1; Myc; medulloblastoma

PMID:
27449089
PMCID:
PMC5288228
DOI:
10.18632/oncotarget.10692
[Indexed for MEDLINE]
Free PMC Article

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