分子靶向泛素化——一种EGFR-TKI获得性耐药肺癌治疗新方法的研究

Nonsmall cell lung cancer (NSCLC) is notoriously known as one of the most widespread death causes among malignant tumors. The epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs) are molecularly targeted drugs used for the treatment of NSCLC. In clinical trials, dramatic responses have been observed in some cases soon after the initiation of treatment. Despite this, acquired resistance to EGFR-TKI treatment almost inevitably develops and shapes the most serious contraint for the clinical application. To date, several major mechanisms of acquired resistance have been experimentally proven, including secondary T790M mutation of the EGFR gene, amplification of the MET gene, activation of ERBB3, and overexpression of HGF. The ubiquitin-proteasome system (UPS) is a major pathway through which the intracellular proteins are degraded. Due to the critical roles of ubiquitination and the ubiquitinmediated proteolysis in tumorigenesis and cell growth, targeting the components involved in these processes is a powerful approach for cancer therapy.In terms of the aforementioned mechanisms of acquired resistance, we are plannning to reconstruct a novel E3 ubiquitin-protein ligase, which orients EGFR (T790M), ERBB3 and MET for destruction. It is further attempted to suppress the biological activity of EGFR-TKI resistant lung cancer cells or reverse their resistance to EGFR-TKI by interfering multiple targeted proteins. With the completion of this study, we could provide innovative approaches to remedying lung cancer patients with acquired EGFR-TKI resistance, as well as enrich the theory of targeted treatment to lung cancer.

非小细胞肺癌是目前全世界最常见和死亡率最高的恶性肿瘤。尽管靶向治疗药物EGFR-TKIs对部分非小细胞肺癌患者疗效明确，但是随着药物的使用，获得性耐药已成为严重限制其应用的首要问题。目前已证实的主要耐药机制有：EGFR（T790M）基因突变，ERBB3异常活化，MET基因异常扩增，HGF过表达等。泛素-蛋白酶体途径是一种内源蛋白降解方式，目前直接干预泛素-蛋白酶体系统或利用泛素化系统对癌蛋白进行靶向降解是肿瘤治疗领域的一种新策略。我们的前期研究表明，利用该策略可以有效降解肺癌细胞EGFR并抑制肿瘤生长。本项目我们拟针对肺癌耐药机制，通过重构可同时针对EGFR（T790M）、ERBB3和MET的泛素连接酶E3，靶向结合并泛素化上述耐药相关蛋白，实现多靶点干预和抑制肺癌恶性表型、逆转肺癌细胞耐药。本项目将为EGFR-TKI获得性耐药的肺癌治疗提供新的思路，并进一步丰富肺癌靶向治疗理论。

非小细胞肺癌是目前全世界最常见和死亡率最高的恶性肿瘤。尽管靶向治疗药物EGFR-TKIs对部分非小细胞肺癌患者疗效明确，但是随着药物的使用，获得性耐药已成为严重限制其应用的首要问题。目前已证实的主要耐药机制有：EGFR（T790M）基因突变，ERBB3异常活化，MET基因异常扩增，HGF过表达等。泛素-蛋白酶体途径是一种内源蛋白降解方式，目前直接干预泛素-蛋白酶体系统或利用泛素化系统对癌蛋白进行靶向降解是肿瘤治疗领域的一种新策略。本项目中我们利用该策略有效降解肺癌细胞EGFR（T790M）、ERBB3和MET等关键分子，实现针对肿瘤细胞的多靶点干预、抑制了肺癌细胞的恶性表型、逆转肺癌细胞耐药。本项目为EGFR-TKI获得性耐药的肺癌治疗提供新的思路，并进一步丰富肺癌靶向治疗理论。