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.