Current cancer drug targets · 2026
Targeting Oncogenic HER2 Mutations by Neratinib-induced HER2 Ubiquitination and Degradation in Breast Cancer.
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Zhang Yingqiu, Meng Xuesong, Hong Yueshun, Su Xin, Zhu Yue, Li Jiayu, Hu Jie, Cheng Shaoxuan, Yang Dian, Liu Shuyan, Zhang Jinrui, Liu Han
Аннотация
BACKGROUND: Recent advances have revealed oncogenic HER2 mutations as an alternative tumorigenic mechanism independent of HER2 overexpression. Certain HER2 mutations confer resistance to current HER2-targeted therapies.
OBJECTIVE: Based on our previous finding that neratinib promotes HER2 endocytic degradation, its inhibitory effects were examined on drug-resistant oncogenic HER2 mutations.
METHODS: The intracellular distribution of HER2 was observed by immunofluorescence. The expression levels of HER2, pAKT, and pMEK with or without neratinib treatment were investigated by Western blotting. Proliferation was assessed using MTT, colony formation, and wound-healing assays. The tumorigenic potential of HER2 mutations was assessed in vivo. The effects of neratinib on HER2 mutants were investigated by colony and spheroid formation assays, and HER2 ubiquitination and intracellular localization were examined by immunoprecipitation and immunofluorescence, respectively.
RESULTS: HER2 mutations enhanced downstream AKT/MEK signaling and promoted tumor-igenesis in vitro and in vivo. Neratinib effectively suppressed downstream signaling, growth, and spheroid formation in cells expressing oncogenic HER2 mutants, including T733I, L755S, and the exon 16 deletion, which was accompanied by evidently enhanced ubiquitination and internalization of these mutants.
DISCUSSION: Neratinib effectively induces the ubiquitination and degradation of HER2 mutants to suppress oncogenic signaling. This feature provides a mechanistic explanation of neratinib activities against therapy-resistant HER2 mutations.
CONCLUSION: Drug-resistant HER2 mutations can be suppressed by neratinib-induced endocytic degradation, resulting in effective suppression of cancer cell growth.
OBJECTIVE: Based on our previous finding that neratinib promotes HER2 endocytic degradation, its inhibitory effects were examined on drug-resistant oncogenic HER2 mutations.
METHODS: The intracellular distribution of HER2 was observed by immunofluorescence. The expression levels of HER2, pAKT, and pMEK with or without neratinib treatment were investigated by Western blotting. Proliferation was assessed using MTT, colony formation, and wound-healing assays. The tumorigenic potential of HER2 mutations was assessed in vivo. The effects of neratinib on HER2 mutants were investigated by colony and spheroid formation assays, and HER2 ubiquitination and intracellular localization were examined by immunoprecipitation and immunofluorescence, respectively.
RESULTS: HER2 mutations enhanced downstream AKT/MEK signaling and promoted tumor-igenesis in vitro and in vivo. Neratinib effectively suppressed downstream signaling, growth, and spheroid formation in cells expressing oncogenic HER2 mutants, including T733I, L755S, and the exon 16 deletion, which was accompanied by evidently enhanced ubiquitination and internalization of these mutants.
DISCUSSION: Neratinib effectively induces the ubiquitination and degradation of HER2 mutants to suppress oncogenic signaling. This feature provides a mechanistic explanation of neratinib activities against therapy-resistant HER2 mutations.
CONCLUSION: Drug-resistant HER2 mutations can be suppressed by neratinib-induced endocytic degradation, resulting in effective suppression of cancer cell growth.