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Ref Type Journal Article
PMID (27837031)
Authors Haak AJ, Appleton KM, Lisabeth EM, Misek SA, Ji Y, Wade SM, Bell JL, Rockwell CE, Airik M, Krook MA, Larsen SD, Verhaegen M, Lawlor ER, Neubig RR
Title Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma.
Journal Molecular cancer therapeutics
Vol 16
Issue 1
Date 2017 Jan
Abstract Text Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Evidence implicates Rho-activated gene transcription in melanoma metastasis mediated by the nuclear localization of the transcriptional coactivator, myocardin-related transcription factor (MRTF). Here, we highlight a role for Rho and MRTF signaling and its reversal by pharmacologic inhibition using in vitro and in vivo models of human melanoma growth and metastasis. Using two cellular models of melanoma, we clearly show that one cell type, SK-Mel-147, is highly metastatic, has high RhoC expression, and MRTF nuclear localization and activity. Conversely, SK-Mel-19 melanoma cells have low RhoC expression, and decreased levels of MRTF-regulated genes. To probe the dependence of melanoma aggressiveness to MRTF transcription, we use a previously developed small-molecule inhibitor, CCG-203971, which at low micromolar concentrations blocks nuclear localization and activity of MRTF-A. In SK-Mel-147 cells, CCG-203971 inhibits cellular migration and invasion, and decreases MRTF target gene expression. In addition, CCG-203971-mediated inhibition of the Rho/MRTF pathway significantly reduces cell growth and clonogenicity and causes G1 cell-cycle arrest. In an experimental model of melanoma lung metastasis, the RhoC-overexpressing melanoma cells (SK-Mel-147) exhibited pronounced lung colonization compared with the low RhoC-expressing SK-Mel-19. Furthermore, pharmacologic inhibition of the MRTF pathway reduced both the number and size of lung metastasis resulting in a marked reduction of total lung tumor burden. These data link Rho and MRTF-mediated signaling with aggressive phenotypes and support targeting the MRTF transcriptional pathway as a novel approach to melanoma therapeutics. Mol Cancer Ther; 16(1); 193-204. ©2016 AACR.


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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
CCG-203971 CCG-203971 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CCG-203971 CCG-203971 is a small molecule inhibitor that blocks the activity and nuclear localization of MRTF-A, thereby possibly resulting in mitigation of cell migration and metastasis, and decreased tumor growth (PMID: 27837031, PMID: 32665796).
Gene 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 CCG-203971 Preclinical - Cell line xenograft Actionable In a preclinical study, a melanoma cell line treated with CCG-203971 resulted in inhibition of cell migration, invasion, and decreased cell growth in culture, and a reduced tumor burden in xenograft models (PMID: 27837031). 27837031