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Rho Kinase Inhibitors Block Melanoma Cell Migration and Inhibit Metastasis

Sadok, Amine, McCarthy, Afshan, Caldwell, John, Collins, Ian, Garrett, Michelle D., Yeo, Maggie, Hooper, Steven, Sahai, Erik, Kuemper, Sandra, Mardakheh, Faraz K., and others. (2015) Rho Kinase Inhibitors Block Melanoma Cell Migration and Inhibit Metastasis. Cancer Research, 75 (11). pp. 2272-2284. ISSN 0008-5472. (doi:10.1158/0008-5472.CAN-14-2156) (KAR id:50204)

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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.

Item Type: Article
DOI/Identification number: 10.1158/0008-5472.CAN-14-2156
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > School of Biosciences
Depositing User: Michelle Garrett
Date Deposited: 17 Aug 2015 10:15 UTC
Last Modified: 08 Mar 2021 10:01 UTC
Resource URI: (The current URI for this page, for reference purposes)
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