Hyperactivation of HER2-SHCBP1-PLK1 axis promotes tumor cell mitosis and impairs trastuzumab sensitivity to gastric cancer

Wengui Shi, Gengyuan Zhang, Zhijian Ma, Lianshun Li, Miaomiao Liu, Long Qin, Zeyuan Yu, Lei Zhao, Yang Liu, Xue Zhang, Junjie Qin, Huili Ye, Xiangyan Jiang, Huinian Zhou, Hui Sun () and Zuoyi Jiao ()
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Wengui Shi: Lanzhou University Second Hospital
Gengyuan Zhang: Lanzhou University Second Hospital
Zhijian Ma: Lanzhou University
Lianshun Li: Lanzhou University
Miaomiao Liu: Lanzhou University
Long Qin: Lanzhou University Second Hospital
Zeyuan Yu: Lanzhou University Second Hospital
Lei Zhao: Lanzhou University Second Hospital
Yang Liu: Lanzhou University Second Hospital
Xue Zhang: Lanzhou University
Junjie Qin: Lanzhou University Second Hospital
Huili Ye: Lanzhou University Second Hospital
Xiangyan Jiang: Lanzhou University
Huinian Zhou: Lanzhou University Second Hospital
Hui Sun: Lanzhou University Second Hospital
Zuoyi Jiao: Lanzhou University Second Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract Trastuzumab is the backbone of HER2-directed gastric cancer therapy, but poor patient response due to insufficient cell sensitivity and drug resistance remains a clinical challenge. Here, we report that HER2 is involved in cell mitotic promotion for tumorigenesis by hyperactivating a crucial HER2-SHCBP1-PLK1 axis that drives trastuzumab sensitivity and is targeted therapeutically. SHCBP1 is an Shc1-binding protein but is detached from scaffold protein Shc1 following HER2 activation. Released SHCBP1 responds to HER2 cascade by translocating into the nucleus following Ser273 phosphorylation, and then contributing to cell mitosis regulation through binding with PLK1 to promote the phosphorylation of the mitotic interactor MISP. Meanwhile, Shc1 is recruited to HER2 for MAPK or PI3K pathways activation. Also, clinical evidence shows that increased SHCBP1 prognosticates a poor response of patients to trastuzumab therapy. Theaflavine-3, 3’-digallate (TFBG) is identified as an inhibitor of the SHCBP1-PLK1 interaction, which is a potential trastuzumab sensitizing agent and, in combination with trastuzumab, is highly efficacious in suppressing HER2-positive gastric cancer growth. These findings suggest an aberrant mitotic HER2-SHCBP1-PLK1 axis underlies trastuzumab sensitivity and offer a new strategy to combat gastric cancer.

Date: 2021
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DOI: 10.1038/s41467-021-23053-8

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