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Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma

The discovery of the BRAF(V600E) mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to...

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Detalles Bibliográficos
Autores principales: Chan, Xian Yang, Singh, Alamdeep, Osman, Narin, Piva, Terrence J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536016/
https://www.ncbi.nlm.nih.gov/pubmed/28708099
http://dx.doi.org/10.3390/ijms18071527
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author Chan, Xian Yang
Singh, Alamdeep
Osman, Narin
Piva, Terrence J.
author_facet Chan, Xian Yang
Singh, Alamdeep
Osman, Narin
Piva, Terrence J.
author_sort Chan, Xian Yang
collection PubMed
description The discovery of the BRAF(V600E) mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to relapse in patients following treatment with vemurafenib which eventually led to patients’ deaths. It has been proposed that mechanisms of resistance can be due to (1) reactivation of the mitogen-activated protein kinase (MAPK) signalling pathway via secondary mutations, amplification or activation of target kinase(s), (2) the bypass of oncogenic pathway via activation of alternative signalling pathways, (3) other uncharacterized mechanisms. Studies showed that receptor tyrosine kinases (RTK) such as PDGFRβ, IGF1R, EGFR and c-Met were overexpressed in melanoma cells. Along with increased secretion of growth factors such as HGF and TGF-α, this will trigger intracellular signalling cascades. This review discusses the role MAPK and Phosphatidylinositol-3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathways play in the mechanism of resistance of melanomas.
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spelling pubmed-55360162017-08-04 Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma Chan, Xian Yang Singh, Alamdeep Osman, Narin Piva, Terrence J. Int J Mol Sci Review The discovery of the BRAF(V600E) mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to relapse in patients following treatment with vemurafenib which eventually led to patients’ deaths. It has been proposed that mechanisms of resistance can be due to (1) reactivation of the mitogen-activated protein kinase (MAPK) signalling pathway via secondary mutations, amplification or activation of target kinase(s), (2) the bypass of oncogenic pathway via activation of alternative signalling pathways, (3) other uncharacterized mechanisms. Studies showed that receptor tyrosine kinases (RTK) such as PDGFRβ, IGF1R, EGFR and c-Met were overexpressed in melanoma cells. Along with increased secretion of growth factors such as HGF and TGF-α, this will trigger intracellular signalling cascades. This review discusses the role MAPK and Phosphatidylinositol-3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathways play in the mechanism of resistance of melanomas. MDPI 2017-07-14 /pmc/articles/PMC5536016/ /pubmed/28708099 http://dx.doi.org/10.3390/ijms18071527 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Chan, Xian Yang
Singh, Alamdeep
Osman, Narin
Piva, Terrence J.
Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma
title Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma
title_full Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma
title_fullStr Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma
title_full_unstemmed Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma
title_short Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma
title_sort role played by signalling pathways in overcoming braf inhibitor resistance in melanoma
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536016/
https://www.ncbi.nlm.nih.gov/pubmed/28708099
http://dx.doi.org/10.3390/ijms18071527
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