Oncogenic BRAF and NRAS mutations drive human melanoma initiation. We used transgenic zebrafish to model NRAS‐mutant melanoma, and the rapid tumor onset allowed us to study candidate tumor suppressors. We identified P38α‐MAPK14 as a potential tumor suppressor in The Cancer Genome Atlas melanoma cohort of NRAS‐mutant melanomas, and overexpression significantly increased the time to tumor onset in transgenic zebrafish with NRAS‐driven melanoma. Pharmacological activation of P38α‐MAPK14 using anisomycin reduced in vitro viability of melanoma cultures, which we confirmed by stable overexpression of p38α. We observed that the viability of MEK inhibitor resistant melanoma cells could be reduced by combined treatment of anisomycin and MEK inhibition. Our study demonstrates that activating the p38α‐MAPK14 pathway in the presence of oncogenic NRAS abrogates melanoma in vitro and in vivo.

中文翻译：

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在斑马鱼模型和 NRAS 突变的人黑色素瘤细胞中激活 p38-MAPK14 可减少 NRASQ61K 黑色素瘤肿瘤的形成

致癌 BRAF 和 NRAS 突变驱动人类黑色素瘤的发生。我们使用转基因斑马鱼来模拟 NRAS 突变黑色素瘤，快速的肿瘤发作使我们能够研究候选的肿瘤抑制因子。我们将 P38α-MAPK14 鉴定为 NRAS 突变黑色素瘤的癌症基因组图谱黑色素瘤队列中的潜在肿瘤抑制因子，并且过表达显着增加了具有 NRAS 驱动的黑色素瘤的转基因斑马鱼的肿瘤发作时间。使用茴香霉素对 P38α-MAPK14 的药理激活降低了黑色素瘤培养物的体外活力，我们通过 p38α 的稳定过表达证实了这一点。我们观察到，茴香霉素和 MEK 抑制的联合治疗可以降低 MEK 抑制剂抗性黑色素瘤细胞的活力。