外域
曲妥珠单抗
帕妥珠单抗
癌症研究
拉帕蒂尼
ADAM10型
细胞生物学
生物
乳腺癌
癌症
化学
金属蛋白酶
医学
受体
内科学
基质金属蛋白酶
生物化学
去整合素
作者
Muwen Yang,Jun Li,Lingzhi Kong,Shu‐Mei Huang,Li-xin He,Pian Liu,Shuang Mo,Xiwen Lu,Xiao Lin,Yunyun Xiao,Dongni Shi,Xinjian Huang,Boyu Chen,Xiangfu Chen,Ying Ouyang,Jun Li,Chuyong Lin,Libing Song
摘要
Human epidermal growth factor receptor 2–targeted (HER2-targeted) therapy is the mainstay of treatment for HER2+ breast cancer. However, the proteolytic cleavage of HER2, or HER2 shedding, induces the release of the target epitope at the ectodomain (ECD) and the generation of a constitutively active intracellular fragment (p95HER2), impeding the effectiveness of anti-HER2 therapy. Therefore, identifying key regulators in HER2 shedding might provide promising targetable vulnerabilities against resistance. In the current study, we found that upregulation of dolichyl-phosphate N-acetylglucosaminyltransferase (DPAGT1) sustained high-level HER2 shedding to confer trastuzumab resistance, which was associated with poor clinical outcomes. Upon trastuzumab treatment, the membrane-bound DPAGT1 protein was endocytosed via the caveolae pathway and retrogradely transported to the ER, where DPAGT1 induced N-glycosylation of the sheddase — ADAM metallopeptidase domain 10 (ADAM10) — to ensure its expression, maturation, and activation. N-glycosylation of ADAM10 at N267 protected itself from ER-associated protein degradation and was essential for DPAGT1-mediated HER2 shedding and trastuzumab resistance. Importantly, inhibition of DPAGT1 with tunicamycin acted synergistically with trastuzumab treatment to block HER2 signaling and reverse resistance. These findings reveal a prominent mechanism for HER2 shedding and suggest that targeting DPAGT1 might be a promising strategy against trastuzumab-resistant breast cancer.
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