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

Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in <i>NRAS</i>-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% <i>BRAF</i>V600 mutations and ≈30% <i>NRAS</i> mutations). While drugs targeting the MAPK pathway have yielded suc...

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Main Authors: Kathryn M. Appleton, Charuta C. Palsuledesai, Sean A. Misek, Maja Blake, Joseph Zagorski, Kathleen A. Gallo, Thomas S. Dexheimer, Richard R. Neubig
Format: Article
Language:English
Published: MDPI AG 2021-04-01
Series:Cancers
Subjects:
Rho GTPase
MEK inhibitor
resistance
Online Access:https://www.mdpi.com/2072-6694/13/9/2012
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spelling doaj-55e2041ccfe9498c8e7bf323839fa7192021-04-22T23:00:59ZengMDPI AGCancers2072-66942021-04-01132012201210.3390/cancers13092012Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in <i>NRAS</i>-Mutant Melanoma Cell LinesKathryn M. Appleton0Charuta C. Palsuledesai1Sean A. Misek2Maja Blake3Joseph Zagorski4Kathleen A. Gallo5Thomas S. Dexheimer6Richard R. Neubig7Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USADepartment of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USADepartment of Physiology, Michigan State University, East Lansing, MI 48824, USADepartment of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USADepartment of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USADepartment of Physiology, Michigan State University, East Lansing, MI 48824, USADepartment of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USADepartment of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USAThe 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% <i>BRAF</i>V600 mutations and ≈30% <i>NRAS</i> mutations). While drugs targeting the MAPK pathway have yielded success in <i>BRAF</i>V600 mutant melanoma patients, such therapies have been ineffective in patients with <i>NRAS</i> 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 <i>NRAS</i> mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in <i>NRAS</i> 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 <i>NRAS</i> mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in <i>NRAS</i> mutant melanomas.https://www.mdpi.com/2072-6694/13/9/2012Rho GTPaseMEK inhibitorresistance
collection DOAJ
language English
format Article
sources DOAJ
author Kathryn M. Appleton
Charuta C. Palsuledesai
Sean A. Misek
Maja Blake
Joseph Zagorski
Kathleen A. Gallo
Thomas S. Dexheimer
Richard R. Neubig
spellingShingle Kathryn M. Appleton
Charuta C. Palsuledesai
Sean A. Misek
Maja Blake
Joseph Zagorski
Kathleen A. Gallo
Thomas S. Dexheimer
Richard R. Neubig
Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in <i>NRAS</i>-Mutant Melanoma Cell Lines
Cancers
Rho GTPase
MEK inhibitor
resistance
author_facet Kathryn M. Appleton
Charuta C. Palsuledesai
Sean A. Misek
Maja Blake
Joseph Zagorski
Kathleen A. Gallo
Thomas S. Dexheimer
Richard R. Neubig
author_sort Kathryn M. Appleton
title Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in <i>NRAS</i>-Mutant Melanoma Cell Lines
title_short Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in <i>NRAS</i>-Mutant Melanoma Cell Lines
title_full Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in <i>NRAS</i>-Mutant Melanoma Cell Lines
title_fullStr Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in <i>NRAS</i>-Mutant Melanoma Cell Lines
title_full_unstemmed Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in <i>NRAS</i>-Mutant Melanoma Cell Lines
title_sort inhibition of the myocardin-related transcription factor pathway increases efficacy of trametinib in <i>nras</i>-mutant melanoma cell lines
publisher MDPI AG
series Cancers
issn 2072-6694
publishDate 2021-04-01
description 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% <i>BRAF</i>V600 mutations and ≈30% <i>NRAS</i> mutations). While drugs targeting the MAPK pathway have yielded success in <i>BRAF</i>V600 mutant melanoma patients, such therapies have been ineffective in patients with <i>NRAS</i> 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 <i>NRAS</i> mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in <i>NRAS</i> 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 <i>NRAS</i> mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in <i>NRAS</i> mutant melanomas.
topic Rho GTPase
MEK inhibitor
resistance
url https://www.mdpi.com/2072-6694/13/9/2012
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