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Int. J. Mol. Sci. 2017, 18(7), 1527; doi:10.3390/ijms18071527

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

1
School of Health & Biomedical Sciences, RMIT University, Bundoora 3083, Victoria, Australia
2
Department of Immunology, Monash University, Melbourne 3004, Victoria, Australia
3
Department of Pharmacy, University of Queensland, Woolloongabba 4102, Queensland, Australia
*
Author to whom correspondence should be addressed.
Received: 19 June 2017 / Revised: 6 July 2017 / Accepted: 12 July 2017 / Published: 14 July 2017
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
View Full-Text   |   Download PDF [728 KB, uploaded 14 July 2017]   |  

Abstract

The discovery of the BRAFV600E 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. View Full-Text
Keywords: melanoma; cell signalling; BRAF; MAPK; RTK; PI3K-AKT-mTOR melanoma; cell signalling; BRAF; MAPK; RTK; PI3K-AKT-mTOR
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Chan, X.Y.; Singh, A.; Osman, N.; Piva, T.J. Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma. Int. J. Mol. Sci. 2017, 18, 1527.

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