Background

The epidermal growth factor receptor (EGFR) is a key protein involved in cancer development. Monoclonal antibodies targeting EGFR are approved for the treatment of metastatic colorectal cancer (CRC). Despite the beneficial clinical effects observed in subgroups of patients, the acquisition of resistance to treatment remains a major concern. Protein N-glycosylation of cellular receptors is known to regulate physiological processes leading to activation of downstream signaling pathways. In the present study, the role of EGFR-specific terminal ⍺2,6-sialylation was analyzed in modulation of the malignant phenotype of CRC cells and their resistance to monoclonal antibody Cetuximab-based therapy.

Methods

Glycoengineered CRC cell models with specific sialyltransferase ST6GAL1 expression levels were applied to evaluate EGFR activation, cell surface glycosylation and therapeutic response to Cetuximab.

Results

Glycoproteomic analysis revealed EGFR as a major target of ST6Gal1-mediated ⍺2,6-sialylation in a glycosite-specific manner. Mechanistically, CRC cells with increased ST6Gal1 expression and displaying terminal ⍺2,6-sialylation showed a marked resistance to Cetuximab-induced cytotoxicity. Moreover, we found that this resistance was accompanied by downregulation of EGFR expression and its activation.

Conclusions

Our data indicate that EGFR ⍺2,6-sialylation is a key factor in modulating the susceptibility of CRC cells to antibody targeted therapy, thereby disclosing a potential novel biomarker and providing key molecular information for tailor made anti-cancer strategies.

中文翻译：

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表皮生长因子受体的末端α2,6-唾液酸化调节结直肠癌细胞的抗体治疗反应

背景

表皮生长因子受体 (EGFR) 是参与癌症发展的关键蛋白质。靶向 EGFR 的单克隆抗体被批准用于治疗转移性结直肠癌 (CRC)。尽管在患者亚组中观察到有益的临床效果，但获得治疗耐药性仍然是一个主要问题。已知细胞受体的蛋白质N-糖基化可调节导致下游信号通路激活的生理过程。在本研究中，分析了 EGFR 特异性末端 ⍺2,6-唾液酸化在调节 CRC 细胞恶性表型及其对基于西妥昔单抗的单克隆抗体治疗的抗性中的作用。

方法

应用具有特定唾液酸转移酶ST6GAL1表达水平的糖工程 CRC 细胞模型来评估 EGFR 活化、细胞表面糖基化和对西妥昔单抗的治疗反应。

结果

糖蛋白组学分析显示 EGFR 是 ST6Gal1 介导的 ⍺2,6-唾液酸化的主要靶点，以糖位点特异性方式进行。机制上，具有增加的 ST6Gal1 表达和显示末端 ⍺2,6-唾液酸化的 CRC 细胞对西妥昔单抗诱导的细胞毒性具有显着的抗性。此外，我们发现这种抗性伴随着 EGFR 表达的下调及其激活。

结论

我们的数据表明 EGFR ⍺2,6-唾液酸化是调节 CRC 细胞对抗体靶向治疗敏感性的关键因素，从而揭示了一种潜在的新型生物标志物，并为量身定制的抗癌策略提供了关键分子信息。