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

Birch, J. L. et al. (2018) A novel small-molecule inhibitor of MRCK prevents radiation-driven invasion in glioblastoma. Cancer Research, 78(22), pp. 6509-6522. (doi:10.1158/0008-5472.CAN-18-1697) (PMID:30279244)

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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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Drysdale, Professor Martin and Croft, Dr Daniel and Mezna, Dr Mokdad and Holmes, Dr William and Birch, Dr Joanna and Qaisi, Abdulrahman Hussain T and Vallatos, Dr Antoine and Crighton, Dr Diane and Gray, Dr Christopher and Strathdee, Mrs Karen and McConnell, Mrs Patricia and McDonald, Dr Laura and Bower, Dr Justin and Sime, Dr Mairi and Chalmers, Professor Anthony and Gilmour, Dr Lesley and Olson, Professor Michael
Authors: Birch, J. L., Strathdee, K., Gilmour, L., Vallatos, A., McDonald, L., Kouzeli, A., Vasan, R., Qaisi, A. H., Croft, D. R., Crighton, D., Gill, K., Gray, C. H., Konczal, J., Mezna, M., McArthur, D., Schüttelkopf, A. W., McConnell, P., Sime, M., Holmes, W. M., Bower, J., McKinnon, H. J., Drysdale, M., Olson, M. F., and Chalmers, A. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Cancer Research
Publisher:American Association for Cancer Research
ISSN:0008-5472
ISSN (Online):1538-7445
Published Online:02 October 2018
Copyright Holders:Copyright © 2018 American Association for Cancer Research
First Published:First published in Cancer Research 78(22):6509-6522
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
773601Probing the ability of a novel MRCK inhibitor, BDP-0009066, to prolong survival in a pre-clinical model of GlioblastomaAnthony ChalmersCancer Research Technology (CRT)4100887ICS - CLINICAL TRIALS RESEARCH