Reference Detail

Ref Type Journal Article
PMID (25840982)
Authors Sadok A, McCarthy A, Caldwell J, Collins I, Garrett MD, Yeo M, Hooper S, Sahai E, Kuemper S, Mardakheh FK, Marshall CJ
Title Rho kinase inhibitors block melanoma cell migration and inhibit metastasis.
Journal Cancer research
Vol 75
Issue 11
Date 2015 Jun 1
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AT13148 AT13148 6 0
CCT129254 CCT129254 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CCT129254 AT11854 AKT Inhibitor (Pan) - ATP competitive 7 CCT129254 is a small molecule ATP-competitive inhibitor of AKT and Rho kinases, which results in decreased tumor cell migration and metastasis (PMID: 25840982).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown melanoma not applicable AT13148 Preclinical Actionable In a preclinical study, AT13148 inhibited human melanoma cell motility in invasion assays in culture (PMID: 25840982). 25840982
Unknown unknown melanoma not applicable CCT129254 Preclinical - Cell line xenograft Actionable In a preclinical study, CCT129254 inhibited motility of two human melanoma cell lines in invasion assays in culture and inhibited metastasis in a mouse melanoma cell line xenograft model (PMID: 25840982). 25840982