靶向EGFR蛋白降解剂及其在非小细胞肺癌中的应用

Novel strategies to target EGFR proteins for degradation and their applications in non-small cell lung cancer

细胞表皮生长因子受体(EGFR)突变是引起部分非小细胞肺癌(NSCLC)发病的一个主要原因。目前,临床上对具有EGFR突变的NSCLC患者使用的标准治疗方案是使用靶向EGFR的酪氨酸激酶小分子抑制剂药物。然而,患者使用此类小分子抑制剂药物后不可避免地会出现耐药现象,因此临床亟需发展新的技术来克服耐药现象,提升靶向治疗的长期疗效。由于EGFR突变肺癌以及此类肺癌对靶向药物产生耐药后对EGFR突变蛋白具有高度的依赖性,开发新型蛋白降解剂特异性地降解EGFR致病蛋白为治疗肺癌和克服肿瘤耐药提供了一种极有潜力的解决途径。目前,已经有多种靶向EGFR蛋白降解的策略用于清除肺癌细胞中的EGFR蛋白,包括靶向蛋白降解技术(PROTAC)、溶酶体靶向降解技术(LYTAC)和基于EGFR和TRIB3相互作用的订书肽。文章主要就上述三种技术在EGFR蛋白靶向降解中的研究进展进行综述,并对其在NSCLC治疗中的潜在应用进行探讨。

Activating mutations in the kinase domains of EGFR(epidermal growth factor receptor)lead into the occurrence of non-small cell lung cancer.Currently,the standard care for such diseases is to use EGFR-specific tyrosine kinase inhibitor drugs.However,drug resistance inevitably occurs after the treatment with these drugs.Novel strategies are needed to solve these issues to extend patients survival time.Due to the dependency of EGFR mutant lung cancer on EGFR proteins and the critical roles of EGFR protein in drug resistance,targeted degradation of EGFR protein provides a promising strategy to treat such patients.Several novel strategies have been developed lately to target EGFR for degradation in non-small cell lung cancer.The strategies include proteolysis targeting chimeras(PROTACs),lysosome-targeting chimaera(LYTAC)and stapled-peptide.The latest development of these strategies were reviewed and their potential uses in lung cancer treatment were assessed.