Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS -Mutant Melanoma Cell Lines

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% V600 mutations and ≈30% mutations). While drugs targeting the MAPK pathway have yielded success in V600 mutant melanoma patients, such the...

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Published in:Cancers 2021-04, Vol.13 (9), p.2012
Main Authors: Appleton, Kathryn M, Palsuledesai, Charuta C, Misek, Sean A, Blake, Maja, Zagorski, Joseph, Gallo, Kathleen A, Dexheimer, Thomas S, Neubig, Richard R
Format: Article
Language:English
Subjects:
Apoptosis
Cell cycle
Cell viability
Clinical trials
Drug delivery
Gene expression
Kinases
MAP kinase
MEK inhibitors
Melanoma
Metabolic pathways
Metastasis
Mutants
Mutation
Proteins
Skin cancer
Transcription factors
Tumors
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Summary:The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% V600 mutations and ≈30% mutations). While drugs targeting the MAPK pathway have yielded success in V600 mutant melanoma patients, such therapies have been ineffective in patients with mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in mutant melanomas.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13092012