Resistance to FGFR1-targeted therapy leads to autophagy via TAK1/AMPK activation in gastric cancer.

Rui Peng, Yan Chen, Liangnian Wei, Gang Li, Dongju Feng, Siru Liu, Runqiu Jiang, Shaojiang Zheng, Yun Chen

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2020 Nov

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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.

Citation

Rui Peng, Yan Chen, Liangnian Wei, Gang Li, Dongju Feng, Siru Liu, Runqiu Jiang, Shaojiang Zheng, Yun Chen. Resistance to FGFR1-targeted therapy leads to autophagy via TAK1/AMPK activation in gastric cancer. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2020 Nov;23(6):988-1002