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A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition

BACKGROUND: The initial use of BRAF targeted therapeutics in clinical trials has demonstrated encouraging responses in melanoma patients, although a rise in drug-resistant cells capable of advancing malignant disease has been described. The current study uses BRAF(V600E )expressing WM793 melanoma ce...

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Detalles Bibliográficos
Autores principales: Klein, R Matthew, Higgins, Paul J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180434/
https://www.ncbi.nlm.nih.gov/pubmed/21917148
http://dx.doi.org/10.1186/1476-4598-10-114
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author Klein, R Matthew
Higgins, Paul J
author_facet Klein, R Matthew
Higgins, Paul J
author_sort Klein, R Matthew
collection PubMed
description BACKGROUND: The initial use of BRAF targeted therapeutics in clinical trials has demonstrated encouraging responses in melanoma patients, although a rise in drug-resistant cells capable of advancing malignant disease has been described. The current study uses BRAF(V600E )expressing WM793 melanoma cells to derive data aimed at investigating the molecular determinant of cell invasion following treatment with clinical BRAF inhibitors. FINDINGS: Small-molecule inhibitors targeting BRAF reduced MEK1/2-ERK1/2 pathway activation and cell survival; yet, viable cell subpopulations persisted. The residual cells exhibited an elongated cell shape, prominent actin stress fibers and retained the ability to invade 3-D dermal-like microenvironments. BRAF inhibitor treatments were associated with reduced expression of RND3, an antagonist of RHOA activation, and elevated RHOA-dependent signaling. Restoration of RND3 expression or RHOA knockdown attenuated the migratory ability of residual cells without affecting overall cell survival. The invasive ability of BRAF inhibitor treated cells embedded in collagen gels was diminished following RND3 re-expression or RHOA depletion. Conversely, melanoma cell movement in the absence of BRAF inhibition was unaffected by RND3 expression or RHOA depletion. CONCLUSION: These data reveal a novel switch in the requirement for RND3 and RHOA in coordinating the movement of residual WM793 cells that are initially refractive to BRAF inhibitor therapy. These results have important clinical implications because they suggest that combining BRAF inhibitors with therapies that target the invasion of drug-resistant cells could aid in controlling disease relapse.
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spelling pubmed-31804342011-09-27 A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition Klein, R Matthew Higgins, Paul J Mol Cancer Short Communication BACKGROUND: The initial use of BRAF targeted therapeutics in clinical trials has demonstrated encouraging responses in melanoma patients, although a rise in drug-resistant cells capable of advancing malignant disease has been described. The current study uses BRAF(V600E )expressing WM793 melanoma cells to derive data aimed at investigating the molecular determinant of cell invasion following treatment with clinical BRAF inhibitors. FINDINGS: Small-molecule inhibitors targeting BRAF reduced MEK1/2-ERK1/2 pathway activation and cell survival; yet, viable cell subpopulations persisted. The residual cells exhibited an elongated cell shape, prominent actin stress fibers and retained the ability to invade 3-D dermal-like microenvironments. BRAF inhibitor treatments were associated with reduced expression of RND3, an antagonist of RHOA activation, and elevated RHOA-dependent signaling. Restoration of RND3 expression or RHOA knockdown attenuated the migratory ability of residual cells without affecting overall cell survival. The invasive ability of BRAF inhibitor treated cells embedded in collagen gels was diminished following RND3 re-expression or RHOA depletion. Conversely, melanoma cell movement in the absence of BRAF inhibition was unaffected by RND3 expression or RHOA depletion. CONCLUSION: These data reveal a novel switch in the requirement for RND3 and RHOA in coordinating the movement of residual WM793 cells that are initially refractive to BRAF inhibitor therapy. These results have important clinical implications because they suggest that combining BRAF inhibitors with therapies that target the invasion of drug-resistant cells could aid in controlling disease relapse. BioMed Central 2011-09-14 /pmc/articles/PMC3180434/ /pubmed/21917148 http://dx.doi.org/10.1186/1476-4598-10-114 Text en Copyright ©2011 Klein and Higgins; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Short Communication
Klein, R Matthew
Higgins, Paul J
A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition
title A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition
title_full A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition
title_fullStr A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition
title_full_unstemmed A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition
title_short A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition
title_sort switch in rnd3-rhoa signaling is critical for melanoma cell invasion following mutant-braf inhibition
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180434/
https://www.ncbi.nlm.nih.gov/pubmed/21917148
http://dx.doi.org/10.1186/1476-4598-10-114
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