美国哈佛医学院Marcia C. Haigis课题组发现GUK1激活是肺癌的代谢靶点。相关论文于2025年2月6日发表于国际顶尖学术期刊《细胞》杂志上。

课题组对间变性淋巴瘤激酶（ALK）重排（“ALK+”）患者来源的细胞系，进行了磷酸化蛋白质组学筛选，发现鸟苷激酶1 （GUK1）是一种鸟苷二磷酸（GDP）合成酶，是肺癌中ALK信号通路的靶标。

课题组人员证明ALK结合并磷酸化GUK1的酪氨酸74 (Y74)，导致GDP生物合成增加。ALK+患者肿瘤样本的空间成像显示GUK1的磷酸化增强，与鸟嘌呤核苷酸的含量显著相关。

抑制GUK1磷酸化会降低细胞内GDP和鸟苷三磷酸（GTP）池，减少了有丝分裂原活化蛋白激酶（MAPK）信号传导和Ras-GTP装载。一种不能磷酸化的GUK1变体（Y74F），在体内和体外都能降低肿瘤的增殖。除ALK外，肺癌中的其他致癌因子蛋白也调节GUK1的磷酸化。

这些研究有望为通过利用肿瘤基因驱动肺癌中的代谢依赖性，来开发新的治疗方法铺平道路。

附：英文原文

Title: GUK1 activation is a metabolic liability in lung cancer

Author: Jaime L. Schneider, Kiran Kurmi, Yutong Dai, Ishita Dhiman, Shakchhi Joshi, Brandon M. Gassaway, Christian W. Johnson, Nicole Jones, Zongyu Li, Christian P. Joschko, Toshio Fujino, Joao A. Paulo, Satoshi Yoda, Gerard Baquer, Daniela Ruiz, Sylwia A. Stopka, Liam Kelley, Andrew Do, Mari Mino-Kenudson, Lecia V. Sequist, Jessica J. Lin, Nathalie Y.R. Agar, Steven P. Gygi, Kevin M. Haigis, Aaron N. Hata, Marcia C. Haigis

Issue&Volume: 2025-02-06

Abstract: Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged (“ALK+”) patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.

DOI: 10.1016/j.cell.2025.01.024

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00093-5