Resistance to FGFR1-targeted therapy leads to autophagy via TAK1/AMPK activation in gastric cancer
Resistance to FGFR1-targeted therapy leads to autophagy via TAK1/AMPK activation in gastric cancer
复制标题
胃癌中对 FGFR1 靶向治疗的耐药性通过 TAK1/AMPK 激活导致自噬
DOI：
10.1007/s10120-020-01088-y
复制
发表时间：
2020-07-02
期刊：
影响因子：
7.4
通讯作者：
Chen, Yun
中科院分区：
文献类型：
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作者：
Peng, Rui;Chen, Yan;Chen, Yun
背景成纤维细胞生长因子受体1（FGFR 1）在多种肿瘤中表达异常。FGFR抑制剂在几种临床前模型中显示出有希望的治疗价值。然而，已经出现了对FGFR抑制剂耐药的肿瘤，表现出明显的侵袭性转移进展，从而损害了治疗结果;然而，耐药的潜在信号传导机制仍不清楚。方法我们使用两种胃癌（GC）细胞系MGC-803和BGC-823建立了FGFR抑制剂耐药细胞模型。进行RNA-seq以确定亲本和抗性细胞之间的连续细胞转录组变化。我们探讨了耐FGFR抑制剂的机制，使用皮下肿瘤模型和GC患者来源的肿瘤器官型culture.ResultsWe观察到，FGFR 1是高表达的GC和FGFR 1肿瘤耐药细胞系，表现出升高水平的自噬活性。这些耐药细胞的特征在于促进转移性生长所需的上皮-间充质转化（EMT）。在耐药细胞中，FGFR 1抑制剂通过AMPK/mTOR信号激活调节GC细胞自噬，这可以使用药理学抑制剂或必需基因敲除来阻断。此外，TGF-β激活的激酶1（TAK 1）扩增和代谢限制导致AMPK通路激活和自噬。体外和体内结果表明，FGFR抑制剂AZD 4547和TAK 1抑制剂NG 25协同抑制AZD 4547耐药细胞系和患者来源的GC器官型cultures.ConclusionsWe阐明了GC对FGFR 1抑制剂原发性耐药的分子机制，提示抑制FGFR 1和TAK 1信号通路可能为FGFR 1耐药胃癌患者提供一种潜在的新的治疗策略。
BackgroundFibroblast growth factor receptor 1 (FGFR1) is frequently dysregulated in various tumors. FGFR inhibitors have shown promising therapeutic value in several preclinical models. However, tumors resistant to FGFR inhibitors have emerged, compromising therapeutic outcomes by demonstrating markedly aggressive metastatic progression; however, the underlying signaling mechanism of resistance remains unknown.MethodsWe established FGFR inhibitor-resistant cell models using two gastric cancer (GC) cell lines, MGC-803 and BGC-823. RNA-seq was performed to determine the continuous cellular transcriptome changes between parental and resistant cells. We explored the mechanism of resistance to FGFR inhibitor, using a subcutaneous tumor model and GC patient-derived tumor organotypic culture.ResultsWe observed that FGFR1 was highly expressed in GC and FGFR1 inhibitor-resistant cell lines, demonstrating elevated levels of autophagic activity. These resistant cells were characterized by epithelial-mesenchymal transition (EMT) required to facilitate metastatic outgrowth. In drug-resistant cells, the FGFR1 inhibitor regulated GC cell autophagy via AMPK/mTOR signal activation, which could be blocked using either pharmacological inhibitors or essential gene knockdown. Furthermore, TGF-β-activated kinase 1 (TAK1) amplification and metabolic restrictions led to AMPK pathway activation and autophagy. In vitro and in vivo results demonstrated that the FGFR inhibitor AZD4547 and TAK1 inhibitor NG25 synergistically inhibited proliferation and autophagy in AZD4547-resistant cell lines and patient-derived GC organotypic cultures.ConclusionsWe elucidated the molecular mechanisms underlying primary resistance to FGFR1 inhibitors in GC, and revealed that the inhibition of FGFR1 and TAK1 signaling could present a potential novel therapeutic strategy for FGFR1 inhibitor-resistant GC patients.