Rho kinase inhibition by AT13148 blocks pancreatic ductal adenocarinoma invasion and tumor growth

Rath, N. et al. (2018) Rho kinase inhibition by AT13148 blocks pancreatic ductal adenocarinoma invasion and tumor growth. Cancer Research, 78(12), pp. 3321-3336. (doi:10.1158/0008-5472.CAN-17-1339) (PMID:29669760)

Rath, N. et al. (2018) Rho kinase inhibition by AT13148 blocks pancreatic ductal adenocarinoma invasion and tumor growth. Cancer Research, 78(12), pp. 3321-3336. (doi:10.1158/0008-5472.CAN-17-1339) (PMID:29669760)

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Abstract

The high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton. We previously reported that ROCK kinase expression increases with human and mouse pancreatic cancer progression and that conditional ROCK activation accelerates mortality in a genetically modified LSL-KrasG12D; LSL-p53R172H; Pdx1-Cre; (KPC) mouse pancreatic cancer model. In this study, we show that treatment of KPC mouse and human TKCC5 patient-derived pancreatic tumor cells with AT13148, as well as the ROCK selective inhibitors Y27632 and H1152, act comparably in blocking ROCK substrate phosphorylation. AT13148, Y27632, and H1152 induced morphological changes and reduced cellular contractile force generation, motility on pliable discontinuous substrates, and three-dimensional collagen matrix invasion. AT13148 treatment reduced subcutaneous tumor growth and blocked invasion of healthy pancreatic tissue by KPC tumor cells in vivo without affecting proliferation, suggesting a role for local tissue invasion as a contributor to primary tumor growth. These results suggest that AT13148 has anti-tumor properties that may be beneficial in combination therapies or in the adjuvant setting to reduce pancreatic cancer cell invasion and slow primary tumor growth. AT13148 might also have the additional benefit of enabling tumor resection by maintaining separation between tumor and healthy tissue boundaries.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cutiongco, Marie Francene and Munro, Dr June and Michalopoulou, Evdokia and McGarry, Ms Lynn and Rath, Dr Nicola and Gadegaard, Professor Nikolaj and Unbekandt, Dr Mathieu and Sumpton, Mr David and Timpson, Dr Paul and Mackay, Dr Gillian and Olson, Professor Michael and Kamphorst, Dr Jurre
Authors: Rath, N., Munro, J., Cutiongco, M. F., Jagiełło, A., Gadegaard, N., McGarry, L., Unbekandt, M., Michalopoulou, E., Kamphorst, J. J., Sumpton, D., Mackay, G., Vennin, C., Pajic, M., Timpson, P., and Olson, M. F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Cancer Research
Publisher:American Association for Cancer Research
ISSN:0008-5472
ISSN (Online):1538-7445
Published Online:18 April 2018
Copyright Holders:Copyright © 2018 American Association for Cancer Research
First Published:First published in Cancer Research 78(12):3321-3336
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
694461EPSRC Centre for Multiscale soft tissue mechanics with application to heart & cancerRaymond OgdenEngineering and Physical Sciences Research Council (EPSRC)EP/N014642/1M&S - MATHEMATICS
655161The effect of tumour microenvironment on the metabolism of pancreatic cancer cellsJurre KamphorstCancer Research UK (CRUK)17728ICS - BEATSON INSTITUTE FOR CANCER RES.