文章：

ETV6-NTRK3致癌基因融合对分子及信号通路改变的影响

The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations

原文发布日期：24 August 2023

DOI: 10.3390/cancers15174246

类型: Article

开放获取: 是

英文摘要：

Chromosomal translocations creating fusion genes are common cancer drivers. The oncogenic ETV6-NTRK3 (EN) gene fusion joins the sterile alpha domain of the ETV6 transcription factor with the tyrosine kinase domain of the neurotrophin-3 receptor NTRK3. Four EN variants with alternating break points have since been detected in a wide range of human cancers. To provide molecular level insight into EN oncogenesis, we employed a proximity labeling mass spectrometry approach to define the molecular context of the fusions. We identify in total 237 high-confidence interactors, which link EN fusions to several key signaling pathways, including ERBB, insulin and JAK/STAT. We then assessed the effects of EN variants on these pathways, and showed that the pan NTRK inhibitor Selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis defines the molecular framework in which EN oncofusions operate to promote cancer and provides some mechanisms for therapeutics.

摘要翻译： 

染色体易位形成融合基因是常见的癌症驱动因素。致癌性ETV6-NTRK3（EN）基因融合将ETV6转录因子的无菌α结构域与神经营养因子-3受体NTRK3的酪氨酸激酶结构域连接。目前已在不同类型的人类癌症中检测到四种具有不同断裂点的EN变异体。为从分子层面揭示EN致癌机制，我们采用邻近标记质谱技术来界定这些融合蛋白的分子环境。共鉴定出237个高置信度相互作用蛋白，这些蛋白将EN融合体与ERBB、胰岛素及JAK/STAT等多个关键信号通路联系起来。随后我们评估了EN变异体对这些通路的影响，并证明泛NTRK抑制剂Selitrectinib（LOXO-195）能够抑制最常见变异体EN2的致癌活性。这项系统层面的分析明确了EN癌性融合蛋白促进癌症发展的分子框架，并为治疗策略提供了机制依据。

原文链接：

The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations