FGFR4磷酸化ATG5抑制细胞自噬的分子机制及其在调控食管鳞癌对FGFR抑制剂敏感性中的作用

食管鳞癌是中国高发特色肿瘤，预后差，迄今尚无有效靶向药物。我们发现食管鳞癌细胞往往携带FGF19扩增，对FGFR抑制剂敏感；FGF19特异性受体FGFR4可结合并磷酸化自噬关键蛋白ATG5，从而抑制自噬的发生；FGFR抑制剂在抑制食管鳞癌细胞增殖的同时可激活保护性自噬，联用自噬抑制剂后疗效更佳。我们推测FGFR抑制剂解除了FGFR4对ATG5的磷酸化，促进ATG5与ATG12结合而激活保护性自噬；联合抑制自噬因此可有效提高FGFR抑制剂对食管鳞癌细胞的增殖抑制。本项目将利用PDC、PDX等模型来明确FGF19是FGFR抑制剂敏感性标志物；利用免疫共沉淀、体外激酶实验等研究FGFR4磷酸化ATG5而调控自噬的具体机制；探讨FGFR抑制剂与自噬抑制剂联用对食管鳞癌的抑制作用，从而揭示FGFR抑制剂诱导食管鳞癌自噬的分子机制，为FGFR抑制剂在食管鳞癌的临床应用提供实验依据。

Esophageal squamous cell carcinoma (ESCC) with high mortality is particularly prevalent in China and the prognosis is poor. So far, there are no effective targeted drugs approved for ESCC. We found that FGF19-amplificated ESCC is sensitive to FGFR inhibitors. The FGF19 specific receptor, FGFR4, can bind and phosphorylate ATG5 to inhibit autophagy. FGFR inhibitors can induce protective autophagy while inhibiting the proliferation of ESCC. Accordingly, we speculate that FGFR inhibitors promote the binding of ATG5 to ATG12 by releasing the phosphorylation of ATG5 by FGFR4, which induces protective autophagy in ESCC. Combined with inhibition of autophagy could markedly enhance the inhibition of ESCC by FGFR inhibitors. Based on this, we will use PDC, PDX models to identify drug sensitivity biomarkers of FGFR inhibitors, use Co-IP and in vitro kinase experiments to elucidate the specific mechanism of FGFR4 regulating autophagy by phosphorylating ATG5, and to explore the synergistic effect of FGFR inhibitors combined with autophagy inhibitors on ESCC, so as to reveal the molecular mechanism of FGFR inhibitor-induced autophagy in ESCC, and provide experimental basis for the clinical application of FGFR inhibitors in ESCC.