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

Joanna L Birch, Karen Strathdee, Lesley Gilmour, Antoine Vallatos, Laura Mcdonald, Ariadni Kouzeli, Richa Vasan, Abdulrahman Hussain Qaisi, Daniel R Croft, Diane Crighton, Kathryn Gill, Christopher H Gray, Jennifer Konczal, Mokdad Mezna, Duncan Mcarthur, Alexander W Schüttelkopf, Patricia Mcconnell, Mairi Sime, William M Holmes, Justin BowerHeather J Mckinnon, Martin Drysdale, Michael F Olson, Anthony J. Chalmers

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that causes severe neurologic, cognitive, and psychologic 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 although radiotherapy (RT) remains the most effective component of multimodality therapy for patients with GBM, 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 proinvasive 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.
Original languageEnglish
Pages (from-to)6509-6522
JournalCancer Research
Volume78
Issue number22
Early online date2 Oct 2018
DOIs
Publication statusPublished - 30 Nov 2018

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