Targeted Therapy in Melanoma and Mechanisms of Resistance

Abstract

The common mutation BRAFV600 in primary melanomas activates the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway and the introduction of proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors (BRAFi and MEKi) was a breakthrough in the treatment of these cancers. However, 15-20% of tumors harbor primary resistance to this therapy, and moreover, patients develop acquired resistance to treatment. Understanding the molecular phenomena behind resistance to BRAFi/MEKis is indispensable in order to develop novel targeted therapies. Most often, resistance develops due to either the reactivation of the MAPK/ERK pathway or the activation of alternative kinase signaling pathways including phosphatase and tensin homolog (PTEN), neurofibromin 1 (NF-1) or RAS signaling. The hyperactivation of tyrosine kinase receptors, such as the receptor of the platelet-derived growth factor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and the receptor for hepatocyte growth factor (HGF), lead to the induction of the AKT/3-phosphoinositol kinase (PI3K) pathway. Another pathway resulting in BRAFi/MEKi resistance is the hyperactivation of epidermal growth factor receptor (EGFR) signaling or the deregulation of microphthalmia-associated transcription factor (MITF).

Keywords: BRAF; MAPK; MEK; drug resistance; melanoma.

Figure 1

BRAF signaling pathway including abnormal signaling from BRAFV600E mutated proteins. The scheme also shows inhibitors and their targets—drugs approved in melanoma treatment are bolded, we also show other potential inhibitors (drugs in development or registered in other indications). RTK–receptor tyrosine kinase; RTKs–receptor tyrosine kinases; BRAF–proto-oncogene B-Raf; BRAFi–BRAF inhibitors; ARAF–serine/threonine-protein kinase A-Raf; CRAF–RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF; PI3K–phosphoinositide 3-kinases; P–phosphoprotein; MEK–mitogen-activated protein kinase kinase; ERK–extracellular-signal-regulated kinase; COT–mitogen-activated protein kinase kinase kinase 8 or serine/threonine-protein kinase cot-1; MCL-1–induced myeloid leukemia cell differentiation protein Mcl-1; AKT–protein kinase B, also known as Akt; Rb–the retinoblastoma protein; Bad–BCL2 associated agonist of cell death; c-Myc–Myc proto-oncogene protein; c-Jun–Jun-related antigen, isoform C; Ets–ETS transcription factor family; c-Fos–proto-oncogene c-Fos.