PO.ET03.06 · 实验与分子治疗
Q702 增强曲妥珠单抗对 HER2+ 胃癌细胞的疗效
Q702 enhances trastuzumab efficacy for HER2 + gastric cancer cells
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：曲妥珠单抗（Tmab）是一种针对 HER2 扩增的晚期食管胃癌（GC）的有效单克隆抗体。遗憾的是，由于对该药物的原发性和获得性耐药，Tmab 的疗效受到限制。Q702 是一种新型口服小分子，可选择性抑制三种受体酪氨酸激酶：Axl、Mer 和 CSF1R。在此，我们描述了 Tmab 与 Q702 在 HER2+ GC 细胞中的治疗协同作用。
材料与方法：在筛选 37 株 GC 细胞系（J-S Kim 等，Int. J. Mol. Sci. 2024, 25(11), 5975）后，评估了以下 GC 细胞：HER2 扩增阳性（HER2+）且 Tmab 敏感的 NCI-N87 和 OE19，HER2+ 且 Tmab 耐药的 OE33、ESO26、SNU-216、MKN7、YCC19、YCC33 和 YCC38，以及 HER2 阴性的 AGS 和 SNU638。我们通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑（MTT）试验和克隆形成细胞存活试验，评估了这些 GC 细胞对单用曲妥珠单抗或与 Q702 联用的细胞毒性反应。进行了 Western blot 以评估生化变化，尤其是与 HER2 信号通路组分相关的变化。集落数量差异的统计学显著性采用 Kruskal-Wallis 检验确定。
结果：HER2+ 且 Tmab 耐药的 GC 细胞相比 HER2+ 且 Tmab 敏感的 GC 细胞表现出相对更高的 AXL 表达。在克隆形成试验中，Q702 显著减少了集落数量，并在 HER2+ GC 细胞中发挥剂量依赖性作用。此外，我们观察到曲妥珠单抗与 Q702 联合治疗在 HER2+ GC 细胞（无论 Tmab 敏感还是 Tmab 耐药）中诱导了统计学显著的集落减少。与 Q702 联用可导致 Tmab 耐药的 HER2+ 细胞中 HER2 及其下游靶点 AKT 和 ERK 的磷酸化降低。在单用 Tmab 或联合治疗的 HER2 阴性 GC 细胞中未检测到生长抑制。
结论：总体而言，这些数据支持 Q702 可克服 HER2+ GC 细胞对 Tmab 的原发性耐药。
查看英文原文 English abstract
Background: Trastuzumab (Tmab) is an effective monoclonal antibody against advanced esophago-gastric cancers (GCs) with HER2 amplification. Unfortunately, the efficacy of Tmab is limited due to primary and acquired resistance to this agent. Q702 is a novel, orally available small molecule that selectively inhibits three receptor tyrosine kinases: Axl, Mer, and CSF1R. Here, we describe a therapeutic synergism between Tmab and Q702 in HER2+ GC cells.
Material and Methods: After screening 37 GC cell lines (J-S Kim et al Int. J. Mol. Sci. 2024, 25(11), 5975), the following GC cells were evaluated: HER2 amplification -positive (HER2+) and Tmab-sensitive NCI-N87 and OE19, HER2+ Tmab-resistant OE33, ESO26, SNU-216, MKN7, YCC19, YCC33, and YCC38 and HER2 negative AGS and SNU638. We assessed the cytotoxic response of these GC cells to trastuzumab alone or in combination with Q702 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, and clonogenic cell survival assays. Western blots were performed to assess biochemical changes, especially those related with HER2 signaling components. The statistical significance of differences of colony numbers were determined by using the Kruskal-Wallis test.
Results: HER2+ Tmab-resistant GC cells showed relatively higher expression of AXL than HER2+ Tmab-sensitive GC cells. Q702 significantly decreased the number of colonies in clonogenc assays and exerted dose-dependent effects in HER2+ GC cells. Additionally, we observed that treatment with trastuzumab in combination with Q702 induced a statistically significant decrease of the colonies in HER2 + GC cells, both Tmab-sensitive and Tmab-resistant. Combination with Q702 resulted in decreased phosphorylation of HER2 and its downstream targets, AKT and ERK, in Tmab-resistant HER2+ cells. No growth inhibition was detected in HER2-GC cells treated with Tmab alone or combination.
Conclusion: Collectively, these data support that Q702 could overcome primary resistance to Tmab in HER2+ GC cells.
利益披露 Disclosure
M. Kim, None.
Y. Lee,
Qurient Co., Ltd. Employment, Stock, Stock Option.
K. Nam,
Qurient Co., Ltd. Employment, g., Board of Directors, non-salaried role), Stock, Stock Option, Patent, Trademark, Copyright, Other Intellectual Property.
J. Kim,
Qurient Co., Ltd. ).