ST6Gal1 targets the ectodomain of ErbB2 in a site-specific manner and regulates gastric cancer cell sensitivity to trastuzumab

Abstract

The clinical performance of the therapeutic monoclonal antibody trastuzumab in the treatment of ErbB2-positive unresectable gastric cancer (GC) is severely hampered by the emergence of molecular resistance. Trastuzumab’s target epitope is localized within the extracellular domain of the oncogenic cell surface receptor tyrosine kinase (RTK) ErbB2, which is known to undergo extensive N-linked glycosylation. However, the site-specific glycan repertoire of ErbB2, as well as the detailed molecular mechanisms through which specific aberrant glycan signatures functionally impact the malignant features of ErbB2-addicted GC cells, including the acquisition of trastuzumab resistance, remain elusive. Here, we demonstrate that ErbB2 is modified with both α2,6- and α2,3-sialylated glycan structures in GC clinical specimens. In-depth mass spectrometry-based glycomic and glycoproteomic analysis of ErbB2’s ectodomain disclosed a site-specific glycosylation profile in GC cells, in which the ST6Gal1 sialyltransferase specifically targets ErbB2 N-glycosylation sites occurring within the receptor’s trastuzumab-binding domain. Abrogation of ST6Gal1 expression reshaped the cellular and ErbB2-specific glycomes, expanded the cellular half-life of the ErbB2 receptor, and sensitized ErbB2-dependent GC cells to trastuzumab-induced cytotoxicity through the stabilization of ErbB dimers at the cell membrane, and the decreased activation of both ErbB2 and EGFR RTKs. Overall, our data demonstrates that ST6Gal1-mediated aberrant α2,6-sialylation actively tunes the resistance of ErbB2-driven GC cells to trastuzumab.

The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology

“…Furthermore, high expression of ST6GAL1 in CSCs could eventually promote chemo-resistance (137). Indeed, ST6Gal1 has been linked to resistance to a number of agents including gemcitabine (138), cisplatin (139), trastuzumab (140,141) or gefitinib (142), latter of which appears to involve sialylation and activation of EGFR (142).…”

Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia

“…Our studies support this concept, and furthermore indicate that ST6Gal1 in BCP-ALL is neither an oncogene nor a tumor suppressor. This does not exclude an important contribution of ST6Gal1 to the outcome of specific therapies such as those making use of monoclonal antibodies, as described for the EGFR and ErbB2 (59,60). However, detailed analytical glycan studies of sialylation on CD19, CD22, or CD20 glycoproteins before and after treatment with antibodies or CAR Tcells would be needed to determine if ST6Gal1 N-linked a2,6 sialylation is a contributing factor to resistance in B-cell malignancies treated with such immune therapies.…”

Integrated Systems Analysis of the Murine and Human Pancreatic Cancer Glycomes Reveals a Tumor-Promoting Role for ST6GAL1

“…Several of these works found that sialylation of receptors by ST6GAL1 alters their signaling properties ( 8 , 42 , 43 ). In recent work, sialylation by ST6GAL1 of the oncogenic receptor Erb2 was found to mask the epitope of an anticancer antibody, promoting resistance to treatment ( 45 ). Our data reveal the upregulation of ST6GAL1 expression and α-2,6-sialylation in cancerous ducts.…”