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)

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 Vasan, Dr Richa and Vallatos, Dr Antoine and Gray, Dr Christopher and Crighton, Dr Diane and McConnell, Mrs Patricia and Strathdee, Mrs Karen and McDonald, Dr Laura and Bower, Professor Justin and Chalmers, Professor Anthony and Sime, Dr Mairi 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 > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing; College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
77360	1	Probing the ability of a novel MRCK inhibitor, BDP-0009066, to prolong survival in a pre-clinical model of Glioblastoma	Anthony Chalmers	Cancer Research Technology (CRT)	4100887	ICS - CLINICAL TRIALS RESEARCH