RTK Inhibitors in Melanoma: From Bench to Bedside

SIMPLE SUMMARY: Receptor tyrosine kinases (RTKs) have long been demonstrated to play key roles in melanoma development. RTK activation requires dimerization and intracellular tyrosine trans-phosphorylation leading to downstream signaling pathways activation. As RTKs show different structures, mechanism of activation could differ. In this review, we will discuss the structure and specific mechanism of activation of each RTK, and its alteration associated with stage of the disease. Additionally, we summarize the effect of RTK inhibitors tested in preclinical and clinical melanoma studies indicating the reason, the reported results, and the rational approaches for combination strategies based on RTK inhibition in melanoma. ABSTRACT: MAPK (mitogen activated protein kinase) and PI3K/AKT (Phosphatidylinositol-3-Kinase and Protein Kinase B) pathways play a key role in melanoma progression and metastasis that are regulated by receptor tyrosine kinases (RTKs). Although RTKs are mutated in a small percentage of melanomas, several receptors were found up regulated/altered in various stages of melanoma initiation, progression, or metastasis. Targeting RTKs remains a significant challenge in melanoma, due to their variable expression across different melanoma stages of progression and among melanoma subtypes that consequently affect response to treatment and disease progression. In this review, we discuss in details the activation mechanism of several key RTKs: type III: c-KIT (mast/stem cell growth factor receptor); type I: EGFR (Epidermal growth factor receptor); type VIII: HGFR (hepatocyte growth factor receptor); type V: VEGFR (Vascular endothelial growth factor), structure variants, the function of their structural domains, and their alteration and its association with melanoma initiation and progression. Furthermore, several RTK inhibitors targeting the same receptor were tested alone or in combination with other therapies, yielding variable responses among different melanoma groups. Here, we classified RTK inhibitors by families and summarized all tested drugs in melanoma indicating the rationale behind the use of these drugs in each melanoma subgroups from preclinical studies to clinical trials with a specific focus on their purpose of treatment, resulted effect, and outcomes.