表皮生长因子受体（EGFR）突变是非小细胞肺癌（NSCLC）中最常见的驱动突变。对于携带EGFR敏感性突变的晚期NSCLC患者，一线治疗是EGFR酪氨酸激酶抑制剂（EGFR-TKI）。然而，大多数携带EGFR突变的NSCLC患者会在EGFR-TKI治疗中发展出耐药突变。通过进一步研究，EGFR-T790M突变所代表的耐药机制揭示了EGFR突变在EGFR-TKI敏感性上的影响。第三代EGFR-TKI能抑制EGFR敏感性突变和T790M突变。新的突变如EGFR-C797S和EGFR-L718Q的出现可能会降低疗效。寻找克服EGFR-TKI耐药性的新靶点成为一个重要挑战。因此，深入了解EGFR的调控机制对于寻找克服EGFR-TKI药物耐药突变的新靶点是至关重要的。作为一种受体型酪氨酸激酶，EGFR在与配体结合后会经历同源/异源二聚化和自体磷酸化，从而激活多个下游信号通路。有越来越多的证据表明EGFR激酶活性不仅受到磷酸化的影响，还受到多种翻译后修饰（PTMs，如S-骈脂化，S-硝酰化，甲基化等）的影响。在本综述中，我们系统地回顾了不同蛋白质PTMs对EGFR激酶活性及其功能的影响，并建议通过调节多个EGFR位点影响EGFR激酶活性的方法是克服EGFR-TKI耐药突变的潜在靶点。版权所有©2023 Elsevier Ltd。保留所有权利。

Epidermal growth factor receptor (EGFR) mutation is the most common driver mutation in non-small cell lung cancer (NSCLC). The first-line therapy for advanced NSCLC patients with EGFR-sensitive mutation is the EGFR tyrosine kinase inhibitor (EGFR-TKI). However, most NSCLC patients with EGFR mutation will develop resistant mutations in EGFR-TKI therapy. With further studies, resistance mechanisms represented by EGFR-T790M mutations have revealed the impact of EGFR mutations in situ on EGFR-TKIs sensitivity. The third-generation EGFR-TKIs inhibit both EGFR-sensitive mutations and T790M mutations. The emergence of novel mutations such as EGFR-C797S and EGFR-L718Q may decrease efficacy. Searching for new targets to overcome EGFR-TKI resistance becomes a key challenge. Therefore, an in-depth understanding of the regulatory mechanisms of EGFR is essential to find novel targets to overcome drug-resistant mutations in EGFR-TKIs. EGFR, as a receptor-type tyrosine kinase, undergoes homo/heterodimerization and autophosphorylation upon binding to ligands, which activates multiple downstream signaling pathways. Interestingly, there is growing evidence that the kinase activity of EGFR is affected not only by phosphorylation but also by various post-translational modifications (PTMs, such as S-palmitoylation, S-nitrosylation, Methylation, etc.). In this review, we systematically review the effects of different protein PTMs on EGFR kinase activity and its functionality and suggest that influencing EGFR kinase activity by modulating multiple EGFR sites are potential targets to overcome EGFR-TKIs resistance mutations.Copyright © 2023 Elsevier Ltd. All rights reserved.