小分子靶向药物是食管癌治疗的研究重点。申请者一直从事热休克蛋白Hsp90新型小分子抑制剂SNX-2112的抗肿瘤作用机制研究。前期研究发现SNX-2112：①抑制食管癌细胞的活性比顺铂高近300倍，但在裸鼠体内的抑瘤率仅为45%，仍需增强其敏感性；②可引起肌醇需求激酶1（IRE1）等非折叠蛋白反应（UPR）蛋白表达的下调；③siRNA干扰IRE1可使SNX-2112的活性翻倍。基于此，本题拟以抑制IRE1增强SNX-2112药效为切入点，采用细胞生物学、肿瘤药理学等手段：①证实SNX-2112可影响IRE1及其相关蛋白的表达；②抑制IRE1通路后，研究SNX-2112对细胞凋亡等作用机制的影响；③在裸鼠体内，SNX-2112与IRE1抑制剂联合用药，探讨IRE1通路在SNX-2112治疗食管癌中的作用机制。本课题将为阐明调控IRE1增强SNX-2112药效的作用机制提供科学依据。

The development of small molecular targeted drug has become the focus of esophageal cancer treatment. The applicant has been engaged in the anti-tumor mechanism research of SNX-2112, a novel Hsp90 inhibitor. In the previous study, we found that the inhibitory activity of SNX-2112 against esophageal cells was nearly 300 times higher than cisplatin. However, the suppression rate of xenograft tumor growth was only 45%, the sensitivity of which requires to be enhanced. Besides, several unfolded protein response proteins such as inositol-requiring enzyme 1 (IRE1) were down-regulated by SNX-2112. Small interfering RNA targeting IRE1 doubled the anti-esophageal activity of SNX-2112. Therefore, the efficacy of SNX-2112 enhanced by IRE1 inhibition might be a potent therapeutic strategy. Based on these findings, this project will further systematically investigate the function and molecular mechanism of IRE1 pathway regulated by SNX2112 in esophageal cancer cells. Using cell biology and cancer pharmacology experimental technologies, we intend to study the effect of SNX-2112 on the expression of IRE1 and IRE1-related proteins, identify the mechanism of SNX-2112-induced cell apoptosis after inhibition of IRE1, evaluate the anti-cancer activity, and explore the mechanism of SNX-2112 in combination with IRE1 inhibitor in vivo. Our study will provide significant insights into the mechanisms of SNX-2112-induced cell apoptosis enhanced by IRE1 inhibition.