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信号转导和转录激活因子3（STAT3）通过调节非小细胞肺癌中的蛋白质分泌介导癌相关成纤维细胞（CAF）诱导的奥希替尼耐药。

STAT3 mediates CAF-induced osimertinib resistance via regulating protein secretion in non-small cell lung cancer.

作者信息

Fan Xuchen, Wu Sheng, Wu Honglong, Huang Yingying, Tong Xuhui, Yu Meiling, Liu Zhe

机构信息

Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.

School of Pharmacy, Bengbu Medical University, Bengbu, Anhui, China.

出版信息

Front Pharmacol. 2025 Jul 9;16:1546491. doi: 10.3389/fphar.2025.1546491. eCollection 2025.

DOI:10.3389/fphar.2025.1546491
PMID:40703348
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12283998/
Abstract

INTRODUCTION

EGFR-TKI resistance is an important factor limiting the clinical application of targeted drugs in NSCLC, but the mechanism remains unclear. The tumor microenvironment is the internal environment for cancer cells to survive, and it plays an important role in tumor resistance.

METHODS

In vitro assays: CCK-8 assay, wound healing, Transwell and Colony formation assay. Protein expression analyzed via Western blot. In vivo antitumor efficacy assessed by xenograft study. Target expression in tumors confirmed by immunohistochemical staining. Statistical analysis used t-test/ANOVA (p<0.05).

RESULTS

This study discovered that cancer associated fibroblasts (CAFs) in the tumor microenvironment induce Osimertinib resistance in NSCLC, and further study revealed that CAF-induced Osimertinib resistance in NSCLC is realized through its protein secretion. Interestingly, STAT3 is the key factor regulating CAF activation and secretion. Knockdown of STAT3 can block the secretory function of CAF, thereby reversing Osimertinib resistance in lung cancer. Furthermore, we blocked STAT3 activation in CAF with the novel STAT3 small molecule inhibitor LL1. LL1 effectively reversed CAF induced osimertinib resistance in NSCLC.

DISCUSSION

This project contributes to a deeper understanding of the molecular mechanism of tumor microenvironment mediated EGFR-TKI resistance in NSCLC, and provides theoretical basis and experimental data for the development of novel resistance reversal agents against the tumor microenvironment.

摘要

引言

表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）耐药是限制靶向药物在非小细胞肺癌（NSCLC）临床应用的重要因素，但其机制尚不清楚。肿瘤微环境是癌细胞生存的内部环境，在肿瘤耐药中起重要作用。

方法

体外实验：细胞计数试剂盒-8（CCK-8）实验、伤口愈合实验、Transwell实验和集落形成实验。通过蛋白质免疫印迹法分析蛋白质表达。通过异种移植研究评估体内抗肿瘤疗效。通过免疫组织化学染色确认肿瘤中的靶点表达。采用t检验/方差分析进行统计分析（p<0.05）。

结果

本研究发现肿瘤微环境中的癌症相关成纤维细胞（CAFs）可诱导NSCLC对奥希替尼产生耐药，进一步研究表明CAF诱导NSCLC对奥希替尼耐药是通过其蛋白质分泌实现的。有趣的是，信号转导和转录激活因子3（STAT3）是调节CAF活化和分泌的关键因子。敲低STAT3可阻断CAF的分泌功能，从而逆转肺癌对奥希替尼的耐药。此外，我们用新型STAT3小分子抑制剂LL1阻断CAF中STAT3的激活。LL1有效逆转了CAF诱导的NSCLC对奥希替尼的耐药。

讨论

本项目有助于更深入了解肿瘤微环境介导的NSCLC中EGFR-TKI耐药的分子机制，并为开发针对肿瘤微环境的新型耐药逆转剂提供理论依据和实验数据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/a36bb7fb8918/fphar-16-1546491-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/eaf04a46907e/FPHAR_fphar-2025-1546491_wc_abs.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/aa90cb914a56/fphar-16-1546491-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/50dc8af6bf29/fphar-16-1546491-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/4792ef668451/fphar-16-1546491-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/126be3292e13/fphar-16-1546491-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/e2f0a42b1154/fphar-16-1546491-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/49bb15368490/fphar-16-1546491-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/a36bb7fb8918/fphar-16-1546491-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/eaf04a46907e/FPHAR_fphar-2025-1546491_wc_abs.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/aa90cb914a56/fphar-16-1546491-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/50dc8af6bf29/fphar-16-1546491-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/4792ef668451/fphar-16-1546491-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/126be3292e13/fphar-16-1546491-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/e2f0a42b1154/fphar-16-1546491-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/49bb15368490/fphar-16-1546491-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/12283998/a36bb7fb8918/fphar-16-1546491-g007.jpg

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EBioMedicine. 2025 Jun;116:105739. doi: 10.1016/j.ebiom.2025.105739. Epub 2025 May 8.
2
Small Molecule Induces Time-Dependent Inhibition of Stat3 Dimerization and DNA-Binding Activity and Regresses Human Breast Tumor Xenografts.小分子诱导 Stat3 二聚体和 DNA 结合活性的时间依赖性抑制作用，并使人乳腺癌异种移植瘤消退。
Chembiochem. 2024 Nov 18;25(22):e202400351. doi: 10.1002/cbic.202400351. Epub 2024 Oct 23.
3
Fibroblasts generate topographical cues that steer cancer cell migration.
成纤维细胞产生拓扑线索，引导癌细胞迁移。
Sci Adv. 2023 Aug 18;9(33):eade2120. doi: 10.1126/sciadv.ade2120. Epub 2023 Aug 16.
4
Research progress of STAT3-based dual inhibitors for cancer therapy.基于 STAT3 的双重抑制剂治疗癌症的研究进展。
Bioorg Med Chem. 2023 Aug 15;91:117382. doi: 10.1016/j.bmc.2023.117382. Epub 2023 Jun 19.
5
Fibroblasts in cancer: Unity in heterogeneity.癌症中的成纤维细胞：异质中的统一。
Cell. 2023 Apr 13;186(8):1580-1609. doi: 10.1016/j.cell.2023.03.016.
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Biomed Pharmacother. 2022 Dec;156:113959. doi: 10.1016/j.biopha.2022.113959. Epub 2022 Nov 5.
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