METHODS: We utilized an established human pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) with a known NRAS mutation to study the effects of MEK inhibition. We evaluated the effects of trametinib on proliferation, motility, and tumor growth in vivo. We created an intraperitoneal metastatic model of this PDX, characterized both the phenotype and the genotype of the metastatic PDX and again, investigated the effects of MEK inhibition.
RESULTS: We found target engagement with decreased ERK1/2 phosphorylation with trametinib treatment. Trametinib led to decreased in vitro cell growth and motility, and decreased tumor growth and increased animal survival in a murine flank tumor model. Finally, we demonstrated that trametinib was able to significantly decrease gastroenteropancreatic neuroendocrine intraperitoneal tumor metastasis.
CONCLUSIONS: The results of these studies support the further investigation of MEK inhibition in pediatric NRAS mutated solid tumors.
方法:我们利用已建立的具有已知NRAS突变的人类小儿胃肠胰腺神经内分泌样肿瘤患者异种移植物(PDX)来研究MEK抑制作用。我们评估了曲美替尼对增殖的影响,运动性,和体内肿瘤生长。我们建立了PDX的腹膜内转移模型,表征了转移性PDX的表型和基因型,研究了MEK抑制作用。
结果:我们发现在曲美替尼治疗下,ERK1/2磷酸化降低的靶参与。曲美替尼导致体外细胞生长和运动减少,在小鼠侧腹肿瘤模型中,肿瘤生长减少,动物存活率增加。最后,我们证明曲美替尼能够显著减少胃肠胰腺神经内分泌腹膜内肿瘤转移.
结论:这些研究的结果支持MEK抑制在小儿NRAS突变实体瘤中的进一步研究。