OBJECTIVE As an epidermal growth factor, receptor-tyrosine kinase inhibitor (EGFR-TKI), gefitinib demonstrates a good therapeutic effect in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). However, an overwhelming majority of these patients inevitably develop resistance against gefitinib. Unfortunately, the mechanism underlying this phenomenon is still not fully understood. Here we aim to reveal the mechanism of gefitinib resistance in NSCLC induced by FGFR1. MATERIALS AND METHODS We used high-throughput sequencing to compare the mRNA expression profiles of PC9 and PC9-GR (gefitinib-resistant) cells. The clinical significance of fibroblast growth factor receptor 1 (FGFR1) in NSCLC was also investigated using immunohistochemistry and Kaplan-Meier survival analysis. Finally, the in vitro molecular mechanisms were analyzed using confocal laser microscopy, Western blotting, transwell assay, colony formation assay, CCK-8 assay, and apoptosis assay. RESULTS We observed that FGFR1 was highly expressed in NSCLC tissues and was closely associated with poor prognosis. Cytological experiments showed that FGFR1 promoted the proliferation and migration of PC9-GR cells and mediated their resistance to gefitinib. Furthermore, studies aimed at unraveling this mechanism revealed that FGFR1 activated the AKT/mTOR signaling pathway. These findings show that the FGFR1/AKT/mTOR signaling pathway plays a vital role in acquired resistance against gefitinib in NSCLC. CONCLUSION This work provides new evidence that FGFR1 functions as a key regulator of gefitinib resistance, thereby demonstrating its potential as a novel biomarker and therapeutic target for NSCLC.

中文翻译：

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FGFR1 通过激活 NSCLC 中的 AKT/mTOR 通路诱导对吉非替尼的获得性耐药。

目的作为表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），吉非替尼在EGFR突变的非小细胞肺癌（NSCLC）患者中表现出良好的治疗效果。然而，绝大多数这些患者不可避免地会对吉非替尼产生耐药性。不幸的是，这种现象背后的机制仍未完全了解。在这里，我们旨在揭示 FGFR1 诱导的 NSCLC 中吉非替尼耐药的机制。材料和方法 我们使用高通量测序来比较 PC9 和 PC9-GR（吉非替尼耐药）细胞的 mRNA 表达谱。还使用免疫组织化学和 Kaplan-Meier 生存分析研究了 NSCLC 中成纤维细胞生长因子受体 1 (FGFR1) 的临床意义。最后，使用共聚焦激光显微镜、蛋白质印迹、transwell 试验、集落形成试验、CCK-8 试验和细胞凋亡试验分析体外分子机制。结果我们观察到FGFR1在NSCLC组织中高表达，与预后不良密切相关。细胞学实验表明，FGFR1促进了PC9-GR细胞的增殖和迁移，并介导了它们对吉非替尼的耐药性。此外，旨在揭示这一机制的研究表明，FGFR1 激活了 AKT/mTOR 信号通路。这些发现表明，FGFR1/AKT/mTOR 信号通路在 NSCLC 对吉非替尼的获得性耐药中起着至关重要的作用。结论 这项工作提供了新的证据表明 FGFR1 是吉非替尼耐药的关键调节因子，