The polo-like kinase 1 inhibitor volasertib synergistically increases radiation efficacy in glioma stem cells
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Jianwen Dong1,*, Soon Young Park1,*, Nghi Nguyen2, Ravesanker Ezhilarasan3, Emmanuel Martinez-Ledesma1,5, Shaofang Wu1, Verlene Henry1, Yuji Piao1, Ningyi Tiao1, David Brunell2, Clifford Stephan2, Roel Verhaak4,5,6, Erik Sulman3, Veerakumar Balasubramaniyan1 and John F. de Groot1
1Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Institute of Biosciences and Technology, Texas A&M Health Science Center at Houston, Center for Translational Cancer Research, Houston, TX, USA
3Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
*These authors contributed equally to this work
John F. de Groot, email: [email protected]
Keywords: glioblastoma; polo-like kinase 1; volasertib; radiation; sensitization
Received: March 29, 2017 Accepted: December 21, 2017 Published: January 08, 2018
Background: Despite the availability of hundreds of cancer drugs, there is insufficient data on the efficacy of these drugs on the extremely heterogeneous tumor cell populations of glioblastoma (GBM).
Results: The PKIS of 357 compounds was initially evaluated in 15 different GSC lines which then led to a more focused screening of the 21 most highly active compounds in 11 unique GSC lines using HTS screening for cell viability. We further validated the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent and in combination with ionizing radiation (IR). In vitro studies showed that volasertib inhibited cell viability, and high levels of the anti-apoptotic protein Bcl-xL expression were highly correlated with volasertib resistance. Volasertib sensitized GSCs to radiation therapy by enhancing G2/M arrest and by inducing apoptosis. Colony-formation assay demonstrated that volasertib plus IR synergistically inhibited colony formation. In intracranial xenograft mouse models, the combination of volasertib and radiation significantly inhibited GSC tumor growth and prolonged median survival compared with radiation treatment alone due to inhibition of cell proliferation, enhancement of DNA damage, and induction of apoptosis.
Conclusions: Our results reinforce the potential therapeutic efficacy of volasertib in combination with radiation for the treatment of GBM.
Methods: We used high-throughput screening (HTS) to identify drugs, out of 357 compounds in the published Protein Kinase Inhibitor Set, with the greatest efficacy against a panel of glioma stem cells (GSCs), which are representative of the classic cancer genome atlas (TCGA) molecular subtypes.
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