Oncotarget

Research Papers:

Targeting Polo-like kinase 1 in SMARCB1 deleted atypical teratoid rhabdoid tumor

Irina Alimova, Angela M. Pierce, Peter Harris, Andrew Donson, Diane K. Birks, Eric Prince, Ilango Balakrishnan, Nicholas K. Foreman, Marcel Kool, Lindsey Hoffman, Sujatha Venkataraman and Rajeev Vibhakar _

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Oncotarget. 2017; 8:97290-97303. https://doi.org/10.18632/oncotarget.21932

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Abstract

Irina Alimova1, Angela M. Pierce1, Peter Harris1, Andrew Donson1, Diane K. Birks3, Eric Prince1, Ilango Balakrishnan1, Nicholas K. Foreman1,2,3, Marcel Kool4, Lindsey Hoffman1, Sujatha Venkataraman1,2 and Rajeev Vibhakar1,2,3

1Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States

2Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children’s Hospital Colorado, Aurora, CO, United States

3Department of Neurosurgery, University of Colorado Denver, Aurora, CO, United States

4Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

Correspondence to:

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

Keywords: Polo-like kinase 1; ATRT; SMARCB1; volasertib

Received: July 13, 2017    Accepted: August 15, 2017    Published: October 19, 2017

ABSTRACT

Atypical teratoid rhabdoid tumor (ATRT) is an aggressive and malignant pediatric brain tumor. Polo-like kinase 1 (PLK1) is highly expressed in many cancers and essential for mitosis. Overexpression of PLK1 promotes chromosome instability and aneuploidy by overriding the G2-M DNA damage and spindle checkpoints. Recent studies suggest that targeting PLK1 by small molecule inhibitors is a promising approach to tumor therapy. We investigated the effect of PLK1 inhibition in ATRT. Gene expression analysis showed that PLK1 was overexpressed in ATRT patient samples and tumor cell lines. Genetic inhibition of PLK1 with shRNA potently suppressed ATRT cell growth in vitro. Treatment with the PLK1 inhibitor BI 6727 (Volasertib) significantly decreased cell growth, inhibited clonogenic potential, and induced apoptosis. BI6727 treatment led to G2-M phase arrest, consistent with PLK1’s role as a critical regulator of mitosis. Moreover, inhibition of PLK1 by BI6727 suppressed the tumor-sphere formation of ATRT cells. Treatment also significantly decreased levels of the DNA damage proteins Ku80 and RAD51 and increased γ-H2AX expression, indicating that BI 6727 can induce DNA damage. Importantly, BI6727 significantly enhanced radiation sensitivity of ATRT cells. In vivo, BI6727 slowed growth of ATRT tumors and prolonged survival in a xenograft model. PLK1 inhibition is a compelling new therapeutic approach for treating ATRT, and the use of BI6727 should be evaluated in clinical studies.


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