A melanoma molecular disease model

Abstract

While advanced melanoma remains one of the most challenging cancers, recent developments in our understanding of the molecular drivers of this disease have uncovered exciting opportunities to guide personalized therapeutic decisions. Genetic analyses of melanoma have uncovered several key molecular pathways that are involved in disease onset and progression, as well as prognosis. These advances now make it possible to create a "Molecular Disease Model" (MDM) for melanoma that classifies individual tumors into molecular subtypes (in contrast to traditional histological subtypes), with proposed treatment guidelines for each subtype including specific assays, drugs, and clinical trials. This paper describes such a Melanoma Molecular Disease Model reflecting the latest scientific, clinical, and technological advances.

Figure 1. The two major signaling pathways implicated in melanoma are the MAPK pathway (red) and the AKT/PI3K (green) pathway which regulate cell growth, proliferation and cell death.

There is a lot of cross-talk between these pathways and their downstream effectors, which we have classified into 8 pathways for simplicity to account for differences in treatment modalities (e.g. signaling through NRAS could affect both MAPK and AKT/PI3K pathways). The additional 6 pathways are: c-KIT (pink), CDK (blue), GNAQ/GNA11 (brown), MITF (orange), NRAS (yellow), and P53/BCL (purple). The complex relationship among BRAF, ARF/INK4A (via dashed line), p16, and p14ARF connotes an alternative splicing relationship.