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.
Highlights
There are three main types of skin cancer: melanoma, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), the latter two are collectively known as non-melanoma skin cancers (NMSC)
Villanueva et al [43] showed that insulin-like growth factor 1 receptor (IGF1R) was overexpressed in resistant melanoma cells and combined inhibition of IGF1R- and MEK-induced dramatic apoptosis, which suggested that ERK-independent resistance was mediated by IGF1R signalling in BRAF inhibitor (BRAFi)-resistant cells, as a result of the activation of the PI3K-AKT signalling pathway
Straussman et al [44] showed that hepatocyte growth factor (HGF) secreted by the surrounding stromal fibroblasts activated the HGF receptor c-Met, resulting in the reactivation of the mitogen-activated protein kinase (MAPK) and PI3K-AKT-mammalian target of rapamycin (mTOR) signalling pathways in BRAFi-resistant melanoma cells
Summary
There are three main types of skin cancer: melanoma, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), the latter two are collectively known as non-melanoma skin cancers (NMSC). Resistance to BRAFi has predominantly been shown to be related to the reactivation of the MAPK signalling pathway (BRAF-MEK-ERK–BRAF-MAPK/ERK kinase-extracellular signal-regulated kinase), other mechanisms e.g., upregulation of PI3K-AKT-mTOR signalling, increased expression of growth factor receptors on the cell membrane have been shown to be involved [13,14]. It was reported by Rizos et al [15] that up to 40% of melanoma patients had unidentified mechanisms of resistance
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