Melanoma: new insights and new therapies

Abstract

Metastatic melanoma has historically been considered as one of the most therapeutically challenging malignancies. However, for the first time after decades of basic research and clinical investigation, new drugs have produced major clinical responses. The discovery of BRAF mutations in melanoma created the first opportunity to develop oncogene-directed therapy in this disease and led to the development of compounds that inhibit aberrant BRAF activity. A decade later, vemurafenib, an orally available and well-tolerated selective BRAF inhibitor, ushered in a new era of molecular treatments for advanced disease. Additional targets have been identified, and novel agents that impact on various signaling pathways or modulate the immune system hold the promise of a whole new therapeutic landscape for patients with metastatic melanoma. One of the major thrusts in melanoma therapy is now focused on understanding and targeting the network of signal transduction pathways and on attacking elements that underlie the tumor's propensity for growth and chemoresistance. In this article, we review the novel targeted anticancer approaches that are under consideration in melanoma treatment.

Figure 1. Key pathways and therapeutic targets in melanoma

Activation of the receptor tyrosine kinase (RTK)-NRAS-BRAF-MEK-ERK signaling stream is central in a large proportion of melanomas (mels), with BRAF and NRAS being the most commonly activated oncogenes. Upstream of RAS, KIT is amplified or activated in a substantial fraction of melanomas from acral, mucosal (muc), and chronic sun-damaged (CSD) sites. Stimulation of the phosphatidylinositol 3-kinase (PI3K) pathway also occurs in melanomas either through loss of PTEN or activation of AKT3. In addition, GNAQ and GNA11, which encode G-α proteins, are preferentially mutated in ocular melanomas. Downstream effectors of the activated signaling network lead to increased transcription of survival genes by transcription factors and heightened prosurvival signals in the mitochondria (Mito) via regulation of apoptotic proteins (red, proapoptotic; green, prosurvival). In the nucleus, epigenetic silencing of tumor suppressor genes occurs through DNA methylation and/or histone acetylation, which are mediated by DNA methyltransferase (DNMT) and histone deactylase (HDAC), respectively. Targeted agents listed in the light purple boxes inhibit the central pathogenetic pathways at specific points of action and potentially have a therapeutic impact on melanoma. Ac, acetylation (of Histone, Hi); cut, cutaneous; Me, methylation (of DNA); TF, transcription factor.