Inhibition of DPAGT1 suppresses HER2 shedding and trastuzumab resistance in human breast cancer

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...

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Veröffentlicht in:The Journal of clinical investigation 2023-07, Vol.133 (14)
Hauptverfasser: Yang, Muwen, Li, Yue, Kong, Lingzhi, Huang, Shumei, He, Lixin, Liu, Pian, Mo, Shuang, Lu, Xiuqing, Lin, Xi, Xiao, Yunyun, Shi, Dongni, Huang, Xinjian, Chen, Boyu, Chen, Xiangfu, Ouyang, Ying, Li, Jun, Lin, Chuyong, Song, Libing
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Sprache:eng
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Zusammenfassung: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI164428