The incidence of HER2 amplification in advanced gastroesophageal adenocarcinoma (GC) reportedly ranges between 10% and 20%, depending on the population studied and the geographical region. Trastuzumab (Tmab) is the standard treatment for GCs with HER2 amplification. Metformin, a widely used antidiabetic drug, is an activator of AMP kinase that can affect the mTOR signaling pathway. The following GC cells were evaluated: HER2+ NCI-N87, YCC-19, YCC-38, OE19, OE33, and HER2- AGS. The effects of Tmab and metformin on these cell lines were assessed as single agents and in combination using cell viability assays, Western blotting, and xenograft models. Metformin induced phosphorylation of AMP kinase in all tested GC cells and dephosphorylation of mTOR in Tmab-sensitive GC cells. We observed that treatment with Tmab in combination with metformin induced a significant decrease in the number of colonies formed on soft agar by N87, YCC-19, YCC-38, and OE19 cells (88%, 95%, 73%, and 98%, respectively), in comparison to the number formed by control cells or cells in the single-treatment groups. No growth inhibition was detected in OE33 cells treated with Tmab alone. Combination with metformin resulted in decreased phosphorylation of HER2 and its downstream targets, AKT and ERK, in Tmab-sensitive HER2+ cells. Phospho-receptor tyrosine kinase (RTK) arrays were used to profile the phospho-proteome, which demonstrated a synergistic decrease in phosphorylation of EGFR, HER2, and HER3. Furthermore, the combination of Tmab and metformin exhibited enhanced antitumor effects in a xenograft model. Collectively, these data suggest that Tmab and metformin act synergistically in HER2+ GC cells. Since metformin is widely used and relatively non-toxic, its addition to the therapeutic regimen along with Tmab could enhance the clinical efficacy in patients with HER2+ GC.
据报道，晚期胃食管腺癌（GC）中HER2扩增的发生率在10%至20%之间，具体取决于研究人群和地理区域。曲妥珠单抗（Tmab）是治疗HER2扩增型GC的标准疗法。二甲双胍是一种广泛使用的抗糖尿病药物，作为AMP激酶激活剂，能够影响mTOR信号通路。本研究评估了以下GC细胞系：HER2阳性的NCI-N87、YCC-19、YCC-38、OE19、OE33以及HER2阴性的AGS。通过细胞活力测定、蛋白质印迹分析和异种移植模型，评估了Tmab和二甲双胍作为单药及联合用药对这些细胞系的影响。二甲双胍在所有测试的GC细胞中均诱导了AMP激酶的磷酸化，并在Tmab敏感的GC细胞中引起mTOR的去磷酸化。我们观察到，与对照组或单药治疗组相比，Tmab联合二甲双胍处理显著减少了N87、YCC-19、YCC-38和OE19细胞在软琼脂上形成的集落数量（分别减少88%、95%、73%和98%）。在单独使用Tmab处理的OE33细胞中未检测到生长抑制。在Tmab敏感的HER2阳性细胞中，联合二甲双胍降低了HER2及其下游靶点AKT和ERK的磷酸化水平。通过磷酸化受体酪氨酸激酶（RTK）阵列对磷酸化蛋白质组进行分析，结果显示EGFR、HER2和HER3的磷酸化水平出现协同性降低。此外，在异种移植模型中，Tmab与二甲双胍联合用药表现出增强的抗肿瘤效果。综上所述，这些数据表明Tmab与二甲双胍在HER2阳性GC细胞中具有协同作用。鉴于二甲双胍的广泛使用性和相对较低的毒性，将其与Tmab联合纳入治疗方案可能增强HER2阳性GC患者的临床疗效。
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