Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate immunity that ablated detectable nevocytes, fully prevented melanoma, and regressed human giant nevus xenografts. These findings reveal nevus mechanistic vulnerabilities and suggest opportunities for topical interventions that may alter the therapeutic options for children with congenital giant nevi.

巨大的先天性黑色素细胞痣是NRAS驱动的增殖可能覆盖高达 80% 的体表。它们最危险的后果是发展为黑色素瘤。这种风险通常会在儿童时期引发先发制人的广泛手术切除，从而产生严重的终生挑战。我们已经提出了临床前模型，包括多个基因工程小鼠和异种移植的人类病变，这使得能够测试局部应用的药物制剂以避免手术。小鼠模型允许识别增生性与衰老性痣阶段以及针对两者的治疗。这些痣概括了人类先天性巨痣的组织学和分子特征，包括黑色素瘤转化的风险。皮肤给药的 MEK、PI3K 和 c-KIT 抑制剂或促炎方酸二丁酯 (SADBE) 实现了主要消退。SADBE 触发了先天免疫，消除了可检测到的新生细胞，完全预防了黑色素瘤，并使人类巨痣异种移植物退化。这些发现揭示了痣机制的弱点，并提出了局部干预的机会，这些干预可能会改变先天性巨大痣儿童的治疗选择。