靶向抑制IRE1/XBP1增强组蛋白去乙酰化酶抑制剂抗食管癌敏感性机制研究

组蛋白去乙酰化酶抑制剂（HDACi）在血液瘤治疗中已取得突破，是表观遗传学药物在癌症治疗中的首次成功，但对实体瘤的效果不佳、且机制不明。前期研究中发现：HDAC在实体瘤组织异常表达，且显著影响患者生存期；但HDACi对实体瘤细胞不敏感，体内的食管癌抑瘤率仅为26.8%；高通量筛选发现，IRE1抑制剂可协同增强HDACi活性，该原创性发明已获专利授权；RNA干扰实验首次证明，HDACi在食管癌细胞中激活的IRE1/XBP1通路可促存活，但在血液瘤细胞中却无影响。因此我们推测IRE1/XBP1的保护性激活可能是HDACi治疗实体瘤不敏感的重要原因。本项目利用细胞生物学、肿瘤药理学等方法，探讨HDACi如何激活细胞中的IRE1/XBP1通路？阐明抑制IRE1/XBP1增强HDACi体内外抗食管癌敏感性的机制。有望揭示HDACi治疗实体瘤失败的关键机制，为其临床治疗提供新的理论依据和联用策略。

Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies, which represent the first breakthrough of epigenetic-based cancer therapy. However, why HDAC inhibition responded poorly in solid tumors remains elusive. Our previous studies showed that, HADCs were abnormally expressed in solid tumors such as esophageal carcinoma (EC), liver hepatoma carcinoma (LIHC), and lung adenocarcinoma (LUAD), and might be used for predicting survival outcomes of patients. But the solid tumor inhibition rate of panobinostat was only 26.8% in nude mice. Through high-throughput screening, IRE1 inhibitor enhanced the anti-solid tumor activity of HDACi, which had successfully obtained the national invention patent authorization. We demonstrated for the first time that HDACi could activate the IRE1 / XBP1 pathway in esophageal cancer cells, but there was no significant change in multiple myeloma cells. Therefore, we speculate that the protective activation of IRE1 / XBP1 may be an important reason for the insensitivity of HDACI to solid tumors. In this study, we investigate, (1) how HDACi activates the IRE1/XBP1 pathway in solid tumor cells, especially in esophageal cancer cells, by using cell biology and tumor pharmacology methods? (2) the mechanism of action of inhibiting IRE1 / XBP1 in enhancing the anti-esophageal cancer sensitivity of HDACi in vitro and in vivo. Our results provide mechanistic insights into the ineffectiveness of HDACi and identify therapeutic strategies that may be implemented in solid tumors, especially in EC.