Preclinical evidence for employing MEK inhibition in NRAS mutated pediatric gastroenteropancreatic neuroendocrine-like tumors

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2024-07-02 DOI:10.1016/j.tranon.2024.102045

Colin H. Quinn , Andee M. Beierle , Adele P. Williams , Raoud Marayati , Laura V. Bownes , Hooper R. Market , Michael E. Erwin , Jamie M. Aye , Jerry E. Stewart , Elizabeth Mroczek-Musulman , Karina J. Yoon , Elizabeth A. Beierle

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引用次数: 0

Abstract

Background

Pediatric gastroenteropancreatic neuroendocrine tumors are exceedingly rare, resulting in most pediatric treatment recommendations being based on data derived from adults. Trametinib is a kinase inhibitor that targets MEK1/2 and has been employed in the treatment of cancers harboring mutations in the Ras pathway.

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.

Abstract Image

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在 NRAS 突变的小儿胃肠胰神经内分泌样肿瘤中使用 MEK 抑制剂的临床前证据。

背景：小儿胃肠胰神经内分泌肿瘤极为罕见，因此大多数小儿治疗建议都是基于成人的数据。曲美替尼是一种针对MEK1/2的激酶抑制剂，已被用于治疗Ras通路突变的癌症：我们利用一种已知存在 NRAS 突变的人小儿胃肠胰神经内分泌样肿瘤患者衍生异种移植（PDX）来研究 MEK 抑制的效果。我们评估了曲美替尼对增殖、运动和体内肿瘤生长的影响。我们创建了腹膜内转移模型，描述了转移PDX的表型和基因型，并再次研究了MEK抑制的效果：结果：我们发现曲美替尼治疗可降低ERK1/2磷酸化的靶点参与。曲美替尼导致体外细胞生长和运动性降低，并在小鼠侧腹肿瘤模型中降低了肿瘤生长，提高了动物存活率。最后，我们证实曲美替尼能够显著减少胃肠胰神经内分泌腹膜内肿瘤转移：这些研究结果支持进一步研究MEK抑制剂在小儿NRAS突变实体瘤中的应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.

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