Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong Province, China.
Clin Transl Oncol. 2023 Mar;25(3):685-695. doi: 10.1007/s12094-022-02974-w. Epub 2022 Oct 25.
Recent studies have shown that the activation of PI3K/AKT signaling pathway is an essential molecular mechanism participating in trastuzumab resistance in HER2 + GC (gastric cancer). However, how can we effectively inhibit AKT activity associated with drug resistance during trastuzumab treatment? Screening inhibitors against the upstream receptors of PI3K/AKT signaling pathway or interacting proteins of members has become an important way.
In this study, western blot, qRT-PCR, CCK8, Co-IP and other techniques were used to explore possible mechanisms participating in trastuzumab resistance in vitro. Besides, the xenograft mouse model and GC tissue samples from patients were used to further validate the in-vitro results.
The expression of XB130 adaptor protein was remarkably increased in GC cell lines resistant to trastuzumab, and knockdown of XB130 could reverse the resistance via downregulating p-AKT. In addition, p-SRC (Tyr416) was increased in resistant cells, which could facilitate the binding of XB130 to PI3K p85α. It was also discovered that XB130 could negatively regulate PTEN gene transcription, and thus a positive feedback loop was formed between SRC-XB130-PTEN.
In HER2 + GC, XB130 contributes to trastuzumab resistance by stimulating the PI3K/AKT signaling pathway through binding to PI3K p85α under the mediation of SRC kinase and regulating PTEN gene transcription, and in turn forming a positive feedback loop between SRC-XB130-PTEN.
最近的研究表明，PI3K/AKT 信号通路的激活是参与曲妥珠单抗耐药的 HER2+GC（胃癌）的重要分子机制。然而，在曲妥珠单抗治疗期间，我们如何有效地抑制与耐药相关的 AKT 活性？筛选针对 PI3K/AKT 信号通路上游受体或成员相互作用蛋白的抑制剂已成为一种重要的方法。
本研究采用 Western blot、qRT-PCR、CCK8、Co-IP 等技术，体外探讨参与曲妥珠单抗耐药的可能机制。此外，还使用了异种移植小鼠模型和来自患者的 GC 组织样本进一步验证了体外结果。
在曲妥珠单抗耐药的 GC 细胞系中，XB130 衔接蛋白的表达明显增加，而 XB130 的敲低可通过下调 p-AKT 逆转耐药。此外，耐药细胞中的 p-SRC（Tyr416）增加，这可促进 XB130 与 PI3K p85α 的结合。还发现 XB130 可负向调节 PTEN 基因转录，从而在 SRC-XB130-PTEN 之间形成正反馈环。
在 HER2+GC 中，XB130 通过 SRC 激酶介导与 PI3K p85α 结合，刺激 PI3K/AKT 信号通路，从而促进曲妥珠单抗耐药，同时通过调节 PTEN 基因转录，在 SRC-XB130-PTEN 之间形成正反馈环。
