Pathways and therapeutic targets in melanoma

Abstract

This review aims to summarize the current knowledge of molecular pathways and their clinical relevance in melanoma. Metastatic melanoma was a grim diagnosis, but in recent years tremendous advances have been made in treatments. Chemotherapy provided little benefit in these patients, but development of targeted and new immune approaches made radical changes in prognosis. This would not have happened without remarkable advances in understanding the biology of disease and tremendous progress in the genomic (and other “omics”) scale analyses of tumors. The big problems facing the field are no longer focused exclusively on the development of new treatment modalities, though this is a very busy area of clinical research. The focus shifted now to understanding and overcoming resistance to targeted therapies, and understanding the underlying causes of the heterogeneous responses to immune therapy.

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

“…However, these agents are not effective in~30% of patients with BRAF V600E melanomas and, of the responders, most relapse within~6 months. 48,49 Importantly, we identified GMPS as a positive regulator of invasive and tumorigenic potential of melanoma cells irrespective of their BRAF/NRAS mutation status (Figures 1 and 2). This evidence combined with the finding that GMPS expression is increased in metastatic melanomas (Figure 3, Supplementary Figure S2), makes of GMPS an attractive candidate for therapeutic targeting.…”

<b><i>BRAF</i></b> V600 Mutational Status in Melanoma Correlates with Cytologic Features in Fine-Needle Aspirate Specimens

“…Recent research suggests that the metastatic dissemination of melanoma occurs as an early event shortly after dermal invasion with the gain of driver mutations including BRAF and copy number alterations [1,2]. The v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) encodes a protein kinase that acts as mediator in the RAS-RAF-MEK-ERK pathway [3]. Approximately 30-72% of melanomas have been associated with a BRAF mutation in the V600 codon [4,5].…”

Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma

“…3 The most common BRAF mutation is V600E, accounting for 70%-80% of BRAF mutations, with other mutations at the V600 position (eg, V600K) accounting for 5% to 15%. 3 The BRAF inhibitor, vemurafenib, was approved in 2011 for the treatment of BRAF V600E Mut MM based on an improvement in OS in a phase 3 trial.…”