Jian Pi Hua Tan Fang Reverses Trastuzumab Resistance of HER2-Positive Gastric Cancer Through PI3K/AKT/mTOR Pathway: Integrating Network Pharmacology, Molecular Docking and Experimental Validation

IF 2.7 4区医学 Q3 IMMUNOLOGY

Immunity, Inflammation and Disease Pub Date : 2025-02-07 DOI:10.1002/iid3.70154

Jia Hu, Wenjing Bu, Yongfang Ding, Xin Li, Bo Zhang, Bo Shen, Cong Wu, Youqi Xu, Xiaoyang Zhang

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Abstract

Background

Currently, trastuzumab resistance significantly impacts the treatment outcome for individuals with HER2-positive gastric cancer. In clinical practice, Jian Pi Hua Tan Fang (JPHTF) has been shown to be effective in preventing recurrences and metastases caused by gastric cancer. Yet, the treatment process remains unknown. We aim to evaluate the potential pharmacological mechanism of JPHTF in interfering with resistance to trastuzumab in HER2-positive gastric cancer (GC).

Methods

In this study, network pharmacology and molecular docking techniques were used to forecast the potential active ingredients, pathways, and targets of JPHTF in overcoming trastuzumab resistance in HER2-positive GC. Then, in vitro models of NCI-N87/TR was developed, and JPHTF-containing serum was utilized for intervention to confirm these crucial targets.

Results

Network pharmacology showed that 92 potential active compounds and 420 therapeutic targets of JPHTF. SRC, EGFR, TP53, and AKT1 were identified as the main targets associated with the PI3K/Akt, MAPK, and Ras pathways, playing crucial roles in angiogenesis, cell apoptosis, cell proliferation, and resistance to chemotherapy in the GC microenvironment. Molecular docking analysis showed that quercetin, formononetin, and luteolin, which are the main active ingredients, exhibit high binding affinity to the central targets PI3K, AKT, and mTOR. In vitro experiment, the JPHTF-containing serum has a significant alleviating effect on reversing trastuzumab resistance and cell apoptotic and proliferation of NCI-N87/TR. Further molecular biological experiments showed that JPHTF could regulate the expression of PI3K/AKT/mTOR pathway.

Conclusion

JPHTF has the ability to overcome trastuzumab resistance in NCI-N87 cells through the regulation of the PI3K/AKT/mTOR pathway.

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健脾化痰方通过PI3K/AKT/mTOR通路逆转her2阳性胃癌曲妥珠单抗耐药：整合网络药理学、分子对接与实验验证

目前，曲妥珠单抗耐药显著影响her2阳性胃癌患者的治疗结果。在临床实践中，健脾化痰方（JPHTF）已被证明能有效预防胃癌的复发和转移。然而，治疗过程仍然未知。我们的目的是评估JPHTF在her2阳性胃癌（GC）中干扰曲妥珠单抗耐药的潜在药理学机制。方法本研究采用网络药理学和分子对接技术预测JPHTF在her2阳性GC中克服曲妥珠单抗耐药的潜在有效成分、途径和靶点。然后，建立NCI-N87/TR体外模型，利用含jphtf的血清进行干预，以确认这些关键靶点。结果网络药理学鉴定出92种潜在活性化合物和420个治疗靶点。SRC、EGFR、TP53和AKT1被确定为与PI3K/Akt、MAPK和Ras通路相关的主要靶点，在GC微环境中血管生成、细胞凋亡、细胞增殖和化疗耐药中发挥重要作用。分子对接分析表明，槲皮素、刺芒柄花素和木犀草素作为主要活性成分，与中心靶点PI3K、AKT和mTOR具有较高的结合亲和力。体外实验中，含jphtf血清对逆转NCI-N87/TR的曲妥珠单抗耐药及细胞凋亡和增殖具有显著的缓解作用。进一步的分子生物学实验表明，JPHTF可以调节PI3K/AKT/mTOR通路的表达。结论JPHTF通过调控PI3K/AKT/mTOR通路，具有克服NCI-N87细胞曲妥珠单抗耐药的能力。

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来源期刊

Immunity, Inflammation and Disease Medicine-Immunology and Allergy

CiteScore

3.60

自引率

0.00%

发文量

146

审稿时长

8 weeks

期刊介绍： Immunity, Inflammation and Disease is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research across the broad field of immunology. Immunity, Inflammation and Disease gives rapid consideration to papers in all areas of clinical and basic research. The journal is indexed in Medline and the Science Citation Index Expanded (part of Web of Science), among others. It welcomes original work that enhances the understanding of immunology in areas including: • cellular and molecular immunology • clinical immunology • allergy • immunochemistry • immunogenetics • immune signalling • immune development • imaging • mathematical modelling • autoimmunity • transplantation immunology • cancer immunology