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

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.

EGF-induced nuclear translocation of SHCBP1 promotes bladder cancer progression through inhibiting RACGAP1-mediated RAC1 inactivation

“…A previous study showed that SHC1 facilitated the development of bladder cancer [ 6 ]. To gain insight into the subset of SHC1-binding proteins and identify the key factor for accelerating tumor progression, we mapped 32 binding proteins associated with SHC1 according to the findings of Wengui Shi et al [ 7 ] and screened for candidates among 32 genes that were differentially expressed between 19 paired bladder cancer and adjacent nontumor tissues (Fig. 1A, B ).…”

“…In addition, nuclear translocation of SHCBP1 is a downstream consequence of HER2 activation, which is dependent on phosphorylation of SHCBP1 at the Ser273 site. Blocking HER2 activation using trastuzumab effectively abolished EGF-induced nuclear localization of SHCBP1 in gastric cancer cells [ 7 ]. In our study, we confirmed that upon EGF induction, SHCBP1 translocates to the nucleus, where it binds to RACGAP1 through its N-terminal domain of amino acids 1 ~ 428, and inhibits the GAP activity of RACGAP1 toward RAC1, causing accelerated EGF-induced cell spreading and increased invasiveness of bladder cancer cells.…”

“…SHCBP1 is closely associated with multiple biological processes and plays an essential role in signaling pathways. Wengui Shi et al [ 7 ] reported that SHCBP1 translocated into the nucleus and interacted with PLK1 for cell mitosis, and they also proved that SHCBP1 can locate at the midbody. Asano et al [ 15 ] reported that SHCBP1 interacted with RACGAP1 at midbody for cytokinesis.…”

Identification of Recurrent Chromosome Breaks Underlying Structural Rearrangements in Mammary Cancer Cell Lines

“…Notably, it was shown that SHCBP1 was significantly up-regulated in breast cancer tissues, and that SHCBP1 knockout inhibited cell proliferation [ 37 ], thus supporting the hypothesis that SHCBP1 is an oncogene. Recently, it was shown that the overproduction of HER2-SHCBP1-PLK1 diminishes the efficacy of trastuzumab in the treatment of HER2-positive gastric cancer by promoting tumor cell mitosis [ 38 ]. Genes in the DNA replication initiation pathway including ORC6 were shown to have prognostic values for numerous cancers including breast cancer [ 39 , 40 , 41 , 42 , 43 ].…”

From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer

“…156 Although several HER-2 targeted drugs have entered clinical trials for patients with GC, the FDA has approved only trastuzumab for first-line treatment of patients with advanced GC. [239][240][241] In addition, HER-2-targeted CAR-T cell therapy for GC is increasingly gaining attention to avoid drug resistance and improve treatment outcomes. 241,242 Song et al produced genetically modified human T cells that express HER-2-specific CAR consisting of CD137 and CD3ζ, 156 which not only recognized and killed HER-2 + GC cells in vitro but also showed effective and persistent antitumor activity against HER-2 + GC xenografts in vivo.…”