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A novel small molecule inhibitor of MRCK prevents radiation-driven invasion in glioblastoma

Birch, Joanna L, Strathdee, Karen, Gilmour, Lesley, Vallatos, Antoine, McDonald, Laura, Kouzeli, Ariadni, Vasan, Richa, Qaisi, Abdulrahman Hussain, Croft, Daniel R, Crighton, Diane, Gill, Kathryn, Gray, Christopher H, Konczal, Jennifer, Mezna, Mokdad, McArthur, Duncan, Schüttelkopf, Alexander W, McConnell, Patricia, Sime, Mairi, Holmes, William M, Bower, Justin, McKinnon, Heather J, Drysdale, Martin, Olson, Michael F and Chalmers, Anthony J. 2018. A novel small molecule inhibitor of MRCK prevents radiation-driven invasion in glioblastoma. Cancer Research 78 (22) , pp. 6509-6522. 10.1158/0008-5472.CAN-18-1697

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Abstract

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that causes severe neurological, cognitive, and psychological symptoms. Symptoms are caused and exacerbated by the infiltrative properties of GBM cells, which enable them to pervade the healthy brain and disrupt normal function. Recent research has indicated that, while radiotherapy (RT) remains the most effective component of multimodality therapy for GBM patients, it can provoke a more infiltrative phenotype in GBM cells that survive treatment. Here we demonstrate an essential role of the actin-myosin regulatory kinase myotonic dystrophy kinase-related CDC42- binding kinase (MRCK) in mediating the pro-invasive effects of radiation. MRCK-mediated invasion occurred via downstream signaling to effector molecules MYPT1 and MLC2. MRCK was activated by clinically relevant doses per fraction of radiation, and this activation was concomitant with an increase in GBM cell motility and invasion. Furthermore, ablation of MRCK activity either by RNAi or by inhibition with the novel small molecule inhibitor BDP-9066 prevented radiation-driven increases in motility both in vitro and in a clinically relevant orthotopic xenograft model of GBM. Crucially, treatment with BDP-9066 in combination with RT significantly increased survival in this model and markedly reduced infiltration of the contralateral cerebral hemisphere.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association for Cancer Research
ISSN: 0008-5472
Date of First Compliant Deposit: 29 October 2018
Date of Acceptance: 17 September 2018
Last Modified: 17 Oct 2019 20:55
URI: http://orca.cf.ac.uk/id/eprint/116257

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