Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

Abstract

Molecular mechanisms involved in pathogenesis of malignant melanoma have been widely studied and novel therapeutic treatments developed in recent past years. Molecular targets for therapy have mostly been recognized in the RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways; small-molecule inhibitors were drawn to specifically target key kinases. Unfortunately, these targeted drugs may display intrinsic or acquired resistance and various evidences suggest that inhibition of a single effector of the signal transduction cascades involved in melanoma pathogenesis may be ineffective in blocking the tumor growth. In this sense, a wider comprehension of the multiple molecular alterations accounting for either response or resistance to treatments with targeted inhibitors may be helpful in assessing, which is the most effective combination of such therapies. In the present review, we summarize the known molecular mechanisms underlying either intrinsic and acquired drug resistance either alternative roads to melanoma pathogenesis, which may become targets for innovative anticancer approaches.

Keywords: alternative therapeutic targets; melanoma pathogenesis; molecular melanoma classification; signal transduction cascades; targeted-therapy resistance.

Figure 1

Major pathways involved in melanoma. Pathways associated with cell proliferation, survival, and differentiation are schematically presented. Arrows, activating signals; interrupted lines, inhibiting signals. AMPK, AMP-activated protein kinase; Aurk, Aurora kinase; BAD, BCL-2 antagonist of cell death; CDK4, cyclin-dependent kinase 4; CDKN2A, cyclin-dependent kinase inhibitor of kinase 2A; ERK, extracellular-related kinase; HGF, hepatocyte growth factor; MITF, microphthalmia-associated transcription factor; MEK, mitogen-activated protein kinase-extracellular-related kinase; PI3K, phosphatidylinositol 3 kinase; PTEN, phosphatase and tensin homolog; RB, retinoblastoma protein; TERT, telomerase reverse transcriptase.

Figure 2

Model of molecular effects after exposure to targeted drugs. Due to molecular heterogeneity of melanoma, treatment with single or combined target inhibitors may induce selective pressure of drug-resistant cells (up) or proliferative block of the different cell populations (bottom).

Figure 3

Main mechanisms of acquired resistance to BRAF–MEK inhibitors. Preexisting (pink balloons) or acquired (green balloons) mechanisms interfering with the antitumor activity of BRAF and/or MEK inhibitors. Arrows, activating signals; interrupted lines, inhibiting signals. CDK, cyclin-dependent kinase; COT, cancer Osaka thyroid kinase; ERK, extracellular-related kinase; FGFR3, fibroblast growth factor receptor 3; HGF, hepatocyte growth factor; IGF-1R, insulin like growth factor-1 receptor; MEK, mitogen-activated protein kinase-extracellular-related kinase; PAX3, paired box homeotic gene 3; PDGFRβ, platelet-derived growth factor receptor-beta; PI3K, phosphatidylinositol 3 kinase; PTEN, phosphatase and tensin homolog RTKs, receptor tyrosine kinases; STAT3, signal transducer and activator of transcription 3.

Figure 4

Model of cell phenotype switching. Interaction between intracellular and microenvironmental factors may determine a continuous switch from a proliferative to an invasive state in melanoma cells during tumor progression.