Novel Biomarkers and Druggable Targets in Advanced Melanoma

SIMPLE SUMMARY: Immunotherapy and targeted therapy represent effective therapeutic opportunities that radically changed the available armamentarium for the treatment of melanoma. In about 50% of patients with advanced disease, long-term survival can be achieved; unfortunately, the other half of patients still have limited benefit from such innovative therapies and experience complications that affect their quality of life. Affordable, reliable and easily-to-detect biomarkers are urgently needed to facilitate the decision-making process, in order to identify patients best suited to receive immune or targeted therapy, with the aims of reducing toxicities, enhancing efficacy and preventing recurrences. ABSTRACT: Immunotherapy with Ipilimumab or antibodies against programmed death (ligand) 1 (anti-PD1/PDL1), targeted therapies with BRAF-inhibitors (anti-BRAF) and their combinations significantly changed melanoma treatment options in both primary, adjuvant and metastatic setting, allowing for a cure, or at least long-term survival, in most patients. However, up to 50% of those with advance or metastatic disease still have no significant benefit from such innovative therapies, and clinicians are not able to discriminate in advance neither who is going to respond and for how long nor who is going to develop collateral effects and which ones. However, druggable targets, as well as affordable and reliable biomarkers are needed to personalize resources at a single-patient level. In this manuscript, different molecules, genes, cells, pathways and even combinatorial algorithms or scores are included in four biomarker chapters (molecular, immunological, peripheral and gut microbiota) and reviewed in order to evaluate their role in indicating a patient’s possible response to treatment or development of toxicities.