Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth
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 huma...
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| Vydáno v: | Cancer research (Chicago, Ill.) Ročník 78; číslo 12; s. 3321 |
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| Hlavní autoři: | , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
15.06.2018
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| ISSN: | 1538-7445, 1538-7445 |
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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
; (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 morphologic 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
without affecting proliferation, suggesting a role for local tissue invasion as a contributor to primary tumor growth. These results suggest that AT13148 has antitumor 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.
Preclinical evaluation of a small-molecule ROCK inhibitor reveals significant effects on PDAC invasion and tumor growth, further validating ROCK kinases as viable therapeutic targets in pancreatic cancer.
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| AbstractList | 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
; (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 morphologic 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
without affecting proliferation, suggesting a role for local tissue invasion as a contributor to primary tumor growth. These results suggest that AT13148 has antitumor 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.
Preclinical evaluation of a small-molecule ROCK inhibitor reveals significant effects on PDAC invasion and tumor growth, further validating ROCK kinases as viable therapeutic targets in pancreatic cancer.
. 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 morphologic 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 antitumor 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.Significance: Preclinical evaluation of a small-molecule ROCK inhibitor reveals significant effects on PDAC invasion and tumor growth, further validating ROCK kinases as viable therapeutic targets in pancreatic cancer. Cancer Res; 78(12); 3321-36. ©2018 AACR.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 morphologic 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 antitumor 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.Significance: Preclinical evaluation of a small-molecule ROCK inhibitor reveals significant effects on PDAC invasion and tumor growth, further validating ROCK kinases as viable therapeutic targets in pancreatic cancer. Cancer Res; 78(12); 3321-36. ©2018 AACR. |
| Author | McGarry, Lynn Michalopoulou, Evdokia Jagiełło, Alicja Kamphorst, Jurre J Mackay, Gillian Olson, Michael F Munro, June Gadegaard, Nikolaj Vennin, Claire Unbekandt, Mathieu Pajic, Marina Cutiongco, Marie Francene Sumpton, David Rath, Nicola Timpson, Paul |
| Author_xml | – sequence: 1 givenname: Nicola surname: Rath fullname: Rath, Nicola organization: Cancer Research UK Beatson Institute, Glasgow, United Kingdom – sequence: 2 givenname: June surname: Munro fullname: Munro, June organization: Cancer Research UK Beatson Institute, Glasgow, United Kingdom – sequence: 3 givenname: Marie Francene surname: Cutiongco fullname: Cutiongco, Marie Francene organization: Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow, United Kingdom – sequence: 4 givenname: Alicja surname: Jagiełło fullname: Jagiełło, Alicja organization: Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow, United Kingdom – sequence: 5 givenname: Nikolaj surname: Gadegaard fullname: Gadegaard, Nikolaj organization: Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow, United Kingdom – sequence: 6 givenname: Lynn surname: McGarry fullname: McGarry, Lynn organization: Cancer Research UK Beatson Institute, Glasgow, United Kingdom – sequence: 7 givenname: Mathieu surname: Unbekandt fullname: Unbekandt, Mathieu organization: Cancer Research UK Beatson Institute, Glasgow, United Kingdom – sequence: 8 givenname: Evdokia surname: Michalopoulou fullname: Michalopoulou, Evdokia organization: Cancer Research UK Beatson Institute, Glasgow, United Kingdom – sequence: 9 givenname: Jurre J surname: Kamphorst fullname: Kamphorst, Jurre J organization: Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom – sequence: 10 givenname: David surname: Sumpton fullname: Sumpton, David organization: Cancer Research UK Beatson Institute, Glasgow, United Kingdom – sequence: 11 givenname: Gillian surname: Mackay fullname: Mackay, Gillian organization: Cancer Research UK Beatson Institute, Glasgow, United Kingdom – sequence: 12 givenname: Claire surname: Vennin fullname: Vennin, Claire organization: St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, Australia – sequence: 13 givenname: Marina surname: Pajic fullname: Pajic, Marina organization: St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, Australia – sequence: 14 givenname: Paul surname: Timpson fullname: Timpson, Paul organization: St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, Australia – sequence: 15 givenname: Michael F surname: Olson fullname: Olson, Michael F email: m.olson@beatson.gla.ac.uk organization: Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom |
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| SubjectTerms | 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives 2-Hydroxyphenethylamine - analogs & derivatives 2-Hydroxyphenethylamine - pharmacology 2-Hydroxyphenethylamine - therapeutic use Amides - pharmacology Amides - therapeutic use Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - pathology Cell Line, Tumor - transplantation Cell Movement - drug effects Disease Models, Animal Female HEK293 Cells Humans Male Mice Neoplasm Invasiveness - pathology Neoplasm Invasiveness - prevention & control Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - pathology Phosphorylation - drug effects Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Pyrazoles - pharmacology Pyrazoles - therapeutic use Pyridines - pharmacology Pyridines - therapeutic use rho-Associated Kinases - antagonists & inhibitors rho-Associated Kinases - metabolism Signal Transduction - drug effects |
| Title | Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth |
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