Department of General Surgery, Research Center for Clinical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, 210009, Jiangsu, China.
Key Laboratory of Emergency and Trauma of Ministry of Education, Tumor Institute of the First Affiliated Hospital, Hainan Medical University, Haikou, 571199, China.
Gastric Cancer. 2020 Nov;23(6):988-1002. doi: 10.1007/s10120-020-01088-y. Epub 2020 Jul 2.
Fibroblast 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.
We 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.
We 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.
We 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.
成纤维细胞生长因子受体 1（FGFR1）在多种肿瘤中经常失调。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 抑制剂产生耐药的肿瘤，通过表现出明显侵袭性的转移进展来损害治疗效果；然而，耐药的潜在信号机制尚不清楚。
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 以确定亲本细胞和耐药细胞之间连续的细胞转录组变化。我们使用皮下肿瘤模型和 GC 患者来源的肿瘤器官培养探索 FGFR 抑制剂耐药的机制。
我们观察到 FGFR1 在 GC 和 FGFR1 抑制剂耐药细胞系中高度表达，表现出升高的自噬活性。这些耐药细胞的特征是需要进行上皮-间充质转化（EMT）以促进转移生长。在耐药细胞中，FGFR1 抑制剂通过 AMPK/mTOR 信号激活调节 GC 细胞自噬，这可以通过药理学抑制剂或必需基因敲低来阻断。此外，TGF-β 激活激酶 1（TAK1）扩增和代谢限制导致 AMPK 通路激活和自噬。体内外结果表明，FGFR 抑制剂 AZD4547 和 TAK1 抑制剂 NG25 协同抑制 AZD4547 耐药细胞系和患者来源的 GC 器官培养物中的增殖和自噬。
我们阐明了 GC 中 FGFR1 抑制剂原发性耐药的分子机制，并揭示了抑制 FGFR1 和 TAK1 信号可能为 FGFR1 抑制剂耐药的 GC 患者提供一种新的潜在治疗策略。
