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

• Main Authors: Xian Yang Chan, Alamdeep Singh, Narin Osman, Terrence J. Piva
• Format: Article
• Language: English
• Published: MDPI AG 2017-07-01
• Series: International Journal of Molecular Sciences
• Subjects: melanoma; cell signalling; BRAF; MAPK; RTK; PI3K-AKT-mTOR
• Online Access: https://www.mdpi.com/1422-0067/18/7/1527

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.