中山大学康铁邦团队的一项最新研究报道了溶酶体EGFR作为Rheb GEF发挥作用，不依赖于其激酶活性来激活mTORC1。这一研究成果于2025年4月21日发表在国际顶尖学术期刊《细胞研究》上。

该团队报道了EGFR的顺式mTORC1激活功能，该功能独立于其激酶活性。他们的研究结果表明，溶酶体定位的EGFR是mTORC1激活的关键，其中EGFR物理结合Rheb，作为Rheb的鸟嘌呤交换因子（GEF），其Glu804作为潜在的谷氨酸手指。细胞中EGFR-E804K基因敲入可降低GTP结合的Rheb水平，并显著抑制mTORC1激活、细胞增殖和肿瘤生长。不同的酪氨酸激酶抑制剂对EGFR诱导的mTORC1激活表现出不同的影响，其中阿法替尼可以额外阻断EGFR的GEF活性，对mTORC1激活和细胞生长产生更大的抑制，而厄洛替尼仅针对激酶活性，仅导致轻微的降低。

此外，一种新的小分子BIEGi-1被设计用于同时靶向Rheb-GEF和EGFR激酶活性，并对含有EGFR突变体的细胞的活力显示出强烈的抑制作用。这些发现揭示了细胞生长中的一个基本事件，并提出了一种有希望的对抗EGFR突变癌症的策略。

据了解，EGFR的致癌突变通常导致egf不依赖的组成激活和异常运输，并与包括非小细胞肺癌在内的几种人类恶性肿瘤有关。EGFR突变的一个主要后果是雷帕霉素复合物1 （mTORC1）的机制靶点激活，这需要EGFR激酶活性和下游PI3K/AKT信号传导，导致细胞增殖增加。然而，最近的研究已经阐明了EGFR在细胞存活和癌症进展中的激酶独立作用。

附：英文原文

Title: Lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1

Author: He, Xiaobo, Wang, Qiu-Xia, Wei, Denghui, Lin, Yujie, Zhang, Xia, Wu, Yuanzhong, Qian, Xuexia, Lin, Zhihao, Xiao, Beibei, Wu, Qinxue, Wang, Zhen, Zhou, Fengtao, Wei, Zhihao, Wang, Jingxuan, Gong, Run, Zhang, Ruhua, Zhang, Qingling, Ding, Ke, Gao, Song, Kang, Tiebang

Issue&Volume: 2025-04-21

Abstract: Oncogenic mutations in EGFR often result in EGF-independent constitutive activation and aberrant trafficking and are associated with several human malignancies, including non-small cell lung cancer. A major consequence of EGFR mutations is the activation of the mechanistic target of rapamycin complex 1 (mTORC1), which requires EGFR kinase activity and downstream PI3K/AKT signaling, resulting in increased cell proliferation. However, recent studies have elucidated kinase-independent roles of EGFR in cell survival and cancer progression. Here, we report a cis mTORC1 activation function of EGFR that is independent of its kinase activity. Our results reveal that lysosomal localization of EGFR is critical to mTORC1 activation, where EGFR physically binds Rheb, acting as a guanine exchange factor (GEF) for Rheb, with its Glu804 serving as a potential glutamic finger. Genetic knock-in of EGFR-E804K in cells reduces the level of GTP-bound Rheb, and significantly suppresses mTORC1 activation, cell proliferation and tumor growth. Different tyrosine kinase inhibitors exhibit distinct effects on EGFR-induced mTORC1 activation, with afatinib, which additionally blocks EGFR’s GEF activity, causing a much greater suppression of mTORC1 activation and cell growth, and erlotinib, which targets only kinase activity, resulting in only a slight decrease. Moreover, a novel small molecule, BIEGi-1, was designed to target both the Rheb-GEF and kinase activities of EGFR, and shows a strong inhibitory effect on the viability of cells harboring EGFR mutants. These findings unveil a fundamental event in cell growth and suggest a promising strategy against cancers with EGFR mutations.

DOI: 10.1038/s41422-025-01110-x

Source: https://www.nature.com/articles/s41422-025-01110-x