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

Abstract

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.

Keywords: BRAF; MAPK; PI3K-AKT-mTOR; RTK; cell signalling; melanoma.

Figure 1

Mechanisms of BRAFi resistance converge on constitutive ERK signalling. Regardless of its upstream activator RAS, BRAF^V600E is constantly activated, and vemurafenib treatment was shown to inhibit the kinase. However, the increased secretion of growth factors (HGF and TGF-α) coupled with the overexpression of receptors (PDGFRβ, IGFR1, EGFR and c-Met) trigger the activation of signalling cascades inside melanoma cells that bypasses BRAFV^600E inhibition, which confers resistance to these therapeutic agents. Both MAPK and PI3K-AKT-mTOR pathways are activated and the signal is passed into the nucleus, which triggers phosphorylation of transcription factors, leading to melanoma cells survival and proliferation as well as tumour metastasis and angiogenesis. Description of the abbreviations listed above are contained within this review.

Figure 2

Growth factor activation of the PI3K-AKT-mTOR and MAPK signalling pathways. Figure is adapted from [67]. Description of the abbreviations listed above are contained within this review.