Targeted therapy for melanoma: a primer

Abstract

Melanoma is the most aggressive form of skin cancer. Unfortunately, despite recent improvements for some solid tumors, the prevalence and mortality of melanoma continue to increase. The identification of activating mutations in melanoma, combined with a growing appreciation of the different pattern of genetic changes in the anatomically defined melanoma subtypes, has become the focus of a concerted effort to translate these discoveries into personalized therapeutic approaches for this disease. This article reviews the known mutations, amplifications, and deletions in kinase signaling pathways that have been implicated in melanoma; the prevalence of these genetic events in clinicopathologically defined melanoma subtypes; and the results of clinical trials that use targeted therapy approaches to block aberrantly activated pathways resulting from these mutations. The challenges that must be overcome to achieve improved outcomes with targeted therapies in melanoma in the future are also discussed.

Figure 1. Kinase Signaling Pathways and Targeted Therapies for Melanoma

The diagram illustrates key proteins in the RAS-RAF-MEK-MAPK and the PI3K-AKT kinase cascades. Arrows represent activation, while bars represent inhibition. Genes that are affected by activating mutations in melanoma (BRAF, NRAS, PI3K, C-KIT, and AKT) are shaded; the degree of shading reflects the relative prevalence of these mutations in cutaneous melanomas. Genes that are affected by genetic inactivation (PTEN) are shown with white type against a black background. The feedback regulation of PI3K and AKT by mTORC1 and mTORC2, respectively, is shown by the dashed lines. Classes and examples of targeted therapies against various effectors in the pathways are shown as free text beside the pathways.