Rab43通过调控Mcl-1介导结肠癌细胞对Wee1蛋白激酶抑制剂AZD1775耐药的机制

尽管Wee1蛋白激酶抑制剂AZD1775取得了良好的抗肿瘤作用，但仍存在肿瘤耐药的问题，极大制约了该药物的临床应用。Rab43是一种高尔基体蛋白，在高尔基体内质网物质转运中发挥重要作用。我们前期研究结果显示，AZD1775通过下调抗凋亡蛋白Mcl-1诱导细胞凋亡，在结肠癌细胞中表现出良好的抗肿瘤效果。Rab43在AZD1775获得性耐药细胞系中显著高表达，其表达与Mcl-1水平密切相关，但其调控Mcl-1介导AZD1775耐药的机制尚不明确。本研究拟在前期研究基础上，明确Rab43在结肠癌对AZD1775耐药中的角色，深入探究Rab43对Mcl-1的调控机制，并采用动物模型验证Rab43作为耐药肿瘤治疗的潜在靶点的效果。本课题将为克服肿瘤耐药的难题提供新的靶点选择和理论依据。

Although the Wee1 protein kinase inhibitor AZD1775 has achieved good anti-tumor effects, there is still a problem of tumor resistance, which greatly restricts the clinical application of the drug. Rab43 is a Golgi protein that plays an important role in the protein transport between the endoplasmic reticulum (ER) and Golgi. Our previous results show that AZD1775 induces apoptosis by down-regulating the anti-apoptotic protein Mcl-1, and shows a good anti-tumor effect in colon cancer cells. Rab43 is highly expressed in AZD1775-acquired drug-resistant cell lines, and its expression is strongly correlated with the level of Mcl-1, but the mechanism of its regulation of Mcl-1 to induce AZD1775 resistance is still unclear. This study intends to clarify the role of Rab43 in the resistance of colon cancer to AZD1775 on the basis of the previous research, explore in-depth the regulation mechanism of Rab43 on Mcl-1, and use animal models to verify the effect of Rab43 as a potential target for drug-resistant tumor treatment. This study will provide a new target selection and theoretical basis for overcoming the problem of tumor resistance.