Kim Jin-Soo, Kim Mi Young, Hong Sungyoul
Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea.
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Cancers (Basel). 2023 Sep 28;15(19):4768. doi: 10.3390/cancers15194768.
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，具体取决于所研究的人群和地理区域。曲妥珠单抗（Tmab）是HER2扩增型GC的标准治疗药物。二甲双胍是一种广泛使用的抗糖尿病药物，是AMP激酶的激活剂，可影响mTOR信号通路。对以下GC细胞进行了评估：HER2+ NCI-N87、YCC-19、YCC-38、OE19、OE33和HER2- AGS。通过细胞活力测定、蛋白质印迹和异种移植模型，评估了Tmab和二甲双胍作为单一药物以及联合使用对这些细胞系的影响。二甲双胍在所有测试的GC细胞中诱导AMP激酶磷酸化，并在Tmab敏感的GC细胞中诱导mTOR去磷酸化。我们观察到，与对照细胞或单药治疗组的细胞相比，Tmab联合二甲双胍处理导致N87、YCC-19、YCC-38和OE19细胞在软琼脂上形成的集落数量显著减少（分别为88%、95%、73%和98%）。单独用Tmab处理的OE33细胞未检测到生长抑制。与二甲双胍联合使用导致Tmab敏感的HER2+细胞中HER2及其下游靶点AKT和ERK的磷酸化降低。使用磷酸化受体酪氨酸激酶（RTK）阵列分析磷酸化蛋白质组，结果表明EGFR、HER2和HER3的磷酸化协同降低。此外，Tmab和二甲双胍的联合在异种移植模型中表现出增强的抗肿瘤作用。总体而言，这些数据表明Tmab和二甲双胍在HER2+ GC细胞中具有协同作用。由于二甲双胍广泛使用且相对无毒，将其与Tmab一起添加到治疗方案中可提高HER2+ GC患者的临床疗效。
