AKR1C1调控SQSTM1寡聚化在非小细胞肺癌EGFR TKIs耐药中的作用及机制研究

非小细胞肺癌的发病率和死亡率居高不下。靶向药EGFR TKIs是晚期敏感非小细胞肺癌患者的首选，但其持续发生的耐药问题是治疗失败的直接原因，尚未得到解决。因此亟需探索EGFR TKIs耐药的关键蛋白。申请人前期在非小细胞肺癌及耐药模型中发现AKR1C1显著上调，且与药物治疗患者存活密切相关；敲低AKR1C1增强EGFR TKIs的药效；提示AKR1C1是EGFR TKIs耐药的关键蛋白。同时AKR1C1结合SQSTM1并调控其寡聚化。基于此，本项目将进一步明确AKR1C1调控EGFR TKIs耐药的作用，并深入研究AKR1C1结合SQSTM1的模式，阐明AKR1C1干预SQSTM1的寡聚化功能及作用，以及此分子事件在非小细胞肺癌EGFR TKIs耐药过程中的重要角色。本项目将发现AKR1C1促EGFR TKIs耐药的新生物学功能和特异结合蛋白，为克服EGFR TKIs耐药问题提供新靶点。

Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) have been accepted as the first-line treatment option for advanced Non-small cell lung cancer (NSCLC) cancer patients with sensitive mutation. Unfortunately, drugs resistance leads to treatment failure, which has not been fully solved. Therefore, it is urgent to uncover key driving proteins underlying EGFR TKIs resistance. The applicant found that AKR1C1, highly expressed in the tumor tissue of NSCLC and EGFR TKIs resistant model cells (T4), predicts poor prognosis of patients accepting drugs treatment. AKR1C1 knockdown in NSCLC cell line augmented the efficiency of EGFR TKIs (gefitinib and erlotinib). The applicant also found that EGFR TKIs resistance-promoting effects of AKR1C1 in NSCLC was linked to its regulatory effects on new binding partner SQSTM1. On this basis, this current project will further investigate the role and molecular mechanism of AKR1C1 in promoting EGFR TKIs resistance in NSCLC, clarify its binding pattern with SQSTM1, further uncover its modulation effects on SQSTM1 oligomerisation, and this specific signaling pathway of SQSTM1 autophagy receptor function in this process. In addition, investigate the role of AKR1C1 catalytic activity in EGFR TKIs resistance, SQSTM1 binding and SQSTM1 oligomerisation regulation, so as to disclosure the specific mechanism of AKR1C1 on SQSTM1. Collectively, this project will uncover a catalytic-independent role for AKR1C1 binding with SQSTM1 to promote SQSTM1 oligomerisation and not only reveal a novel functional role of AKR1C1 in EGFR TKIs resistance, but also indicate that AKR1C1 could represent a new potential target to improve EGFR TKIs resistance in NSCLC.