Mutant forms of EGFR promote HER2 trafficking through efficient formation of HER2-EGFR heterodimers
Mutant forms of EGFR promote HER2 trafficking through efficient formation of HER2-EGFR heterodimers
复制标题
EGFR 突变形式通过有效形成 HER2-EGFR 异二聚体促进 HER2 运输
DOI：
10.1016/j.lungcan.2022.11.018
复制
发表时间：
2023
期刊：
影响因子：
5.3
通讯作者：
Okamoto Isamu
中科院分区：
文献类型：
--
作者：
Tsutsumi Hirono;Iwama Eiji;Ibusuki Ritsu;Shimauchi Atsushi;Ota Keiichi;Yoneshima Yasuto;Inoue Hiroyuki;Tanaka Kentaro;Nakanishi Yoichi;Okamoto Isamu
人表皮生长因子受体2（human epidermal growth factor receptor 2，HER 2）是一种同源二聚体，存在于HER 2扩增阳性的癌细胞表面。HER 2在癌细胞withoutHER 2amplification的二聚化，内化，和细胞内运输仍然uncharacterized，however.Materials and methodsHER 2 homodimer和heterodimer检测在各种细胞系中使用的原位邻近连接试验。通过活细胞成像检查了野生型或突变型表皮生长因子受体（EGFR）对HER 2细胞内转运的影响。结果HER 2与EGFR形成异源二聚体后，在HER 2扩增阴性的细胞中，HER 2与EGFR形成异源二聚体，并迅速内化。与没有EGFR激活突变的细胞相比，HER 2-EGFR异源二聚体更丰富，HER 2更有效地转移到溶酶体。T-DM 1在EGFR突变的细胞中表现出很高的细胞毒活性，这表明EGFR的突变形式通过有效地形成HER 2-EGFR异二聚体促进HER 2结合的T-DM 1转移到溶酶体。并且它们为使用HER 2靶向ADC治疗EGFR突变的肺癌提供了理论基础。
IntroductionHuman epidermal growth factor receptor 2 (HER2) forms homodimers and is retained at the surface of cancer cells positive forHER2amplification. The dimerization, internalization, and intracellular trafficking of HER2 in cancer cells withoutHER2amplification have remained uncharacterized, however.Materials and methodsHER2 homodimers and heterodimers were detected in various cell lines with the use of an in situ proximity ligation assay. The effects of wild-type or mutant forms of epidermal growth factor receptor (EGFR) on intracellular trafficking of HER2 were examined by live-cell imaging. The sensitivity of cell lines withoutHER2amplification to ado-trastuzumab emtansine (T-DM1), an anti-HER2 (trastuzumab)–cytotoxic drug conjugate (ADC) was also investigated.ResultsHER2 preferentially formed heterodimers with EGFR rather than homodimers and was rapidly internalized together with EGFR in cells withoutHER2amplification. HER2-EGFR heterodimers were more abundant and HER2 was more efficiently transferred to lysosomes in such cells with than in those withoutEGFRactivating mutations. T-DM1 showed a high cytotoxic efficacy in the cells withEGFRmutations, suggesting that mutant forms of EGFR promote the transfer of HER2-bound T-DM1 to lysosomes through efficient formation of HER2-EGFR heterodimers.ConclusionOur findings reveal that HER2 trafficking is affected by EGFR, especially by mutant forms of the receptor, and they provide a rationale for the use of HER2-targeting ADCs in the treatment ofEGFR-mutated lung cancer.