Kinnunen Matias, Liu Xiaonan, Niemelä Elina, Öhman Tiina, Gawriyski Lisa, Salokas Kari, Keskitalo Salla, Varjosalo Markku
Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland.
Cancers (Basel). 2023 Aug 24;15(17):4246. doi: 10.3390/cancers15174246.
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.
产生融合基因的染色体易位是常见的癌症驱动因素。致癌性ETV6-NTRK3（EN）基因融合将ETV6转录因子的无活性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起来。此后，在多种人类癌症中检测到了四种具有交替断点的EN变体。为了从分子水平深入了解EN的致癌机制，我们采用了邻近标记质谱法来确定融合的分子背景。我们总共鉴定出237个高可信度的相互作用蛋白，它们将EN融合与包括ERBB、胰岛素和JAK/STAT在内的几个关键信号通路联系起来。然后，我们评估了EN变体对这些通路的影响，并表明泛NTRK抑制剂塞利替尼（LOXO-195）可抑制最常见变体EN2的致癌活性。这种系统水平的分析定义了EN致癌融合促进癌症发生的分子框架，并提供了一些治疗机制。
