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: Amine Sadok, Afshan McCarthy, John Caldwell, Ian Collins, Michelle D Garrett, Maggie Yeo, Steven Hooper, Erik Sahai, Sandra Kuemper, Faraz K Mardakheh, Christopher J Marshall
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 11 Pg. 2272-84 (Jun 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25840982 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• AT13148
• Protein Kinase Inhibitors
• Pyrazoles
• 2-Hydroxyphenethylamine
• rho-Associated Kinases

Topics

• 2-Hydroxyphenethylamine (administration & dosage, analogs & derivatives)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Humans
• Melanoma (drug therapy, genetics, pathology)
• Neoplasm Invasiveness (genetics)
• Neoplasm Metastasis
• Phosphorylation
• Protein Kinase Inhibitors (administration & dosage)
• Pyrazoles (administration & dosage)
• Signal Transduction (drug effects)
• rho-Associated Kinases (antagonists & inhibitors, genetics)