☆ 4.8 Article

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

NATURE COMMUNICATIONS (2021)

Journal

NATURE COMMUNICATIONS

Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO

DOI: 10.1038/s41467-021-23053-8

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Funding

National Natural Sciences Foundation of China [31670847]
Talent Introduction Plan of the Lanzhou University Second Hospital [yjrckyqdj-2019-01]
Gansu Provincial Key Research and Development Program [17YF1FA127]
Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital [CY2018-QN01, CY2017-ZD03]
Fundamental Research Funds for the Central Universities [lzujbky-2017-78, lzujbky-2020-ct04]
Scientific Research Projects of Colleges in Gansu Province [2019B-013]

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Abstract

The study demonstrates that HER2 promotes tumorigenesis in gastric cancer by regulating mitotic progression through a Shc1-SHCBP1-PLK1-MISP axis, with TFBG identified as a compound capable of disrupting the SHCBP1/PLK1 interaction and synergizing with trastuzumab.

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. Resistance to Trastuzumab in HER2 gastric cancer patients remains a clinical challenge. In this study, the authors demonstrate that HER2 promotes tumorigenesis in gastric cancer by regulating mitotic progression through a Shc1-SHCBP1-PLK1-MISP axis and they identify a compound, TFBG, able to disrupt SHCBP1/PLK1 interaction and to synergize with trastuzumab.

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Summary: The prevalence of chronic kidney disease (CKD) is increasing, but effective therapies are lacking. This study found that Polo-like kinase 1 (Plk1) is upregulated in CKD patients and mice with unilateral ureteral obstruction (UUO), and its inhibition attenuates obstructive nephropathy by suppressing fibroblast activation through reduced autophagic flux. Plk1 plays a critical role in preserving lysosomal function and preventing partial epithelial-mesenchymal transition (pEMT) in renal tubular epithelial cells via autophagy pathway.

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