title: Rho kinase inhibitors block melanoma cell migration and inhibit metastasis.
abstract: There is an urgent need to identify new therapeutic opportunities for metastatic melanoma. Fragment-based screening has led to the discovery of orally available, ATP-competitive AKT kinase inhibitors, AT13148 and CCT129254. These compounds also inhibit the Rho-kinases ROCK 1 and ROCK 2 and we show they potently inhibit ROCK activity in melanoma cells in culture and in vivo. Treatment of melanoma cells with CCT129254 or AT13148 dramatically reduces cell invasion, impairing both "amoeboid-like" and mesenchymal-like modes of invasion in culture. Intravital imaging shows that CCT129254 or AT13148 treatment reduces the motility of melanoma cells in vivo. CCT129254 inhibits melanoma metastasis when administered 2 days after orthotopic intradermal injection of the cells, or when treatment starts after metastases have arisen. Mechanistically, our data suggest that inhibition of ROCK reduces the ability of melanoma cells to efficiently colonize the lungs. These results suggest that these novel inhibitors of ROCK may be beneficial in the treatment of metastasis.
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom. chris.marshall@icr.ac.uk amine.sadok@icr.ac.uk.
authors.forename: Amine
authors.initials: A
authors.lastname: Sadok
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Afshan
authors.initials: A
authors.lastname: McCarthy
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Caldwell
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Garrett
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Maggie
authors.initials: M
authors.lastname: Yeo
authors.affiliation: Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Hooper
authors.affiliation: Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kuemper
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Faraz K
authors.initials: FK
authors.lastname: Mardakheh
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom. chris.marshall@icr.ac.uk amine.sadok@icr.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Marshall
mesh_terms: D015078:2-Hydroxyphenethylamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C000600307:AT13148; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D015078:2-Hydroxyphenethylamine; D054460:rho-Associated Kinases