OTUD7B去泛素化SLC7A11抑制铁死亡促进肺腺癌EGFR-TKI耐药的机制研究

EGFR-TKI药物能够明显延长肺腺癌EGFR突变患者生存期，而患者长期使用后出现耐药成为该药物的治疗瓶颈，但目前仍有约40%的耐药机制不清。最新研究表明，铁死亡与肿瘤靶向治疗耐药密不可分。我们前期研究发现，在临床标本中，EGFR-TKI耐药与去泛素化酶OTUD7B高表达正相关；在耐药细胞中，OTUD7B可通过去泛素化铁死亡调控因子SLC7A11，诱导细胞铁死亡改变；此外，KYNU也在其调控铁死亡过程中起关键性作用。因此，我们推测：OTUD7B通过去泛素化SLC7A11，与KYNU共同调控SLC7A11，降低铁死亡敏感性，诱导EGFR-TKI耐药。本项目拟通过临床病理标本、分子生物学实验、动物实验等方法，首次研究OTUD7B调控的铁死亡改变在EGFR-TKI耐药中的作用，阐明其OTU域在去泛素化SLC7A11，调控铁死亡中的作用，为肺腺癌EGFR-TKI耐药提供新的理论依据和治疗方法

EGFR-TKI can significantly prolong the survival time of patients with EGFR mutation in lung adenocarcinoma. Drug resistance after long-term use of EGFR-TKI has become a bottleneck in the treatment of EGFR-TKI. Recent studies have shown that ferroptosis is closely related to drug resistance of tumor targeted therapy. Our previous study found that EGFR-TKI resistance was positively correlated with the high expression of deubiquitinase OTUD7B in patients’ samples; OTUD7B could induce ferroptosis through the ubiquitination of ferroptosis regulator SLC7A11 in drug-resistant cells. In addition, KYNU also played a key role in the regulation of ferroptosis. Therefore, we speculate that OTUD7B can induce EGFR-TKI resistance through ubiquitination of SLC7A11, forming a complex with KYNU. This project intends to study the role of ferroptosis regulated by OTUD7B in EGFR-TKI resistance through clinical pathological specimens, molecular biology experiments and animal experiments, which clarify the role of OTU domain in deubiquitination SLC7A11 and KYNU formation complex, so as to provide new theoretical basis and treatment methods for EGFR-TKI resistance of lung adenocarcinoma.