肢端黑色素瘤 (AM) 是一种侵袭性黑色素瘤变体，由手掌、足底和指甲单位黑色素细胞产生。与非肢端皮肤黑色素瘤 (CM) 相比，AM 在生物学上是不同的，在遗传祖先中具有相同的发病率，通常出现在疾病晚期，对治疗的反应较差，总体预后较差。对已发表的基因组和转录组测序的独立分析发现，受体酪氨酸激酶 (RTK) 配体和衔接蛋白在 AM 中经常被扩增、易位和/或过度表达。为了针对这些独特的遗传变化，将斑马鱼肢端黑色素瘤模型暴露于一组窄谱和广谱多 RTK 抑制剂，结果表明 FGFR/VEGFR 双重抑制剂可减少肢端类似黑色素细胞的增殖和迁移。强效泛 FGFR/VEGFR 抑制剂 Lenvatinib 在 AM 患者来源的异种移植 (PDX) 肿瘤中一致诱导肿瘤消退，但仅减缓 CM 模型中的肿瘤生长。与其他多 RTK 抑制剂不同，Lenvatinib 对解离的 AM PDX 肿瘤细胞不具有直接细胞毒性，而是破坏肿瘤结构和血管网络。考虑到建立AM细胞培养系的巨大困难，这些发现表明AM可能比CM对微环境扰动更敏感。总之，FGFR/VEGFR 双重抑制可能是针对 AM 独特生物学的可行治疗策略。

Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis. Independent analysis of published genomic and transcriptomic sequencing identified that receptor tyrosine kinase (RTK) ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. To target these unique genetic changes, a zebrafish acral melanoma model was exposed to a panel of narrow and broad spectrum multi-RTK inhibitors, revealing that dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration. The potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM patient-derived xenograft (PDX) tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks. Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.