Sabbah Malak, Najem Ahmad, Krayem Mohammad, Awada Ahmad, Journe Fabrice, Ghanem Ghanem E
Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium.
Medical Oncolgy Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium.
Cancers (Basel). 2021 Apr 2;13(7):1685. doi: 10.3390/cancers13071685.
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.
丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/AKT）信号通路在黑色素瘤的进展和转移中起关键作用，这些过程受受体酪氨酸激酶（RTK）调控。虽然RTK在一小部分黑色素瘤中发生突变，但在黑色素瘤起始、进展或转移的不同阶段发现有几种受体上调/改变。由于RTK在黑色素瘤进展的不同阶段以及黑色素瘤亚型之间的表达存在差异，这会影响治疗反应和疾病进展，因此靶向RTK在黑色素瘤治疗中仍然是一项重大挑战。在本综述中，我们详细讨论了几种关键RTK的激活机制：III型：c-KIT（肥大/干细胞生长因子受体）；I型：表皮生长因子受体（EGFR）；VIII型：肝细胞生长因子受体（HGFR）；V型：血管内皮生长因子受体（VEGFR），其结构变体、结构域的功能，以及它们的改变及其与黑色素瘤起始和进展的关联。此外，几种靶向同一受体的RTK抑制剂单独或与其他疗法联合进行了测试，在不同黑色素瘤组中产生了不同的反应。在这里，我们按类别对RTK抑制剂进行了分类，并总结了在黑色素瘤中测试的所有药物，指出了从临床前研究到临床试验在每个黑色素瘤亚组中使用这些药物的基本原理，特别关注它们的治疗目的、产生的效果和结果。
