Checkpoint Kinase 1 Expression is an Adverse Prognostic Marker and Therapeutic Target in MYC-driven Medulloblastoma

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Jul 25

PMID 27449089

Citations 13

Authors

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

Rajeev Vibhakar

Affiliations

Soon will be listed here.

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.

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