表皮生长因子受体 (EGFR) 在肿瘤血管生成、分化和迁移等多种与癌症发展相关的机制中起着积极作用。因此，靶向 EGFR 已成为治疗几种癌症的重要方法，包括非小细胞肺癌 (NSCLC)、胰腺癌和胶质母细胞瘤。多种第一、第二和第三代 EGFR 酪氨酸激酶抑制剂 (EGFR-TKIs) 已经证明具有抗癌治疗的有效性。然而，快速的药物耐药性和突变仍然是 EGFR-TKIs 治疗面临的主要挑战。克服由 EGFR 突变引起的内在和获得性耐药性需要进一步探索替代策略并发现新型抑制剂。在本综述中，我们深入探讨了过去20年中取得的突破性发现，并讨论了目前正在进行的努力来解决化疗耐药性问题。我们还重点介绍了发展改进的治疗方法（如第四代 EGFR-TKIs、肽、纳米抗体、PROTACs 等）面临的新挑战、限制和未来发展方向。版权所有 © 2023. Elsevier B.V. 发表。

Epidermal growth factor receptor (EGFR) actively involves in modulation of various cancer progression related mechanisms including angiogenesis, differentiation and migration. Therefore, targeting EGFR has surfaced as a prominent approach for the treatment of several types of cancers, including non-small cell lung cancer (NSCLC), pancreatic cancer, glioblastoma. Various first, second and third generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated effectiveness as an anti-cancer therapeutics. However, rapid development of drug resistance and mutations still remains a major challenge for the EGFR-TKIs therapy. Overcoming from intrinsic and acquired resistance caused by EGFR mutations warrants the further exploration of alternative strategies and discovery of novel inhibitors. In this review, we delve into the breakthrough discoveries have been made in previous 20 years, and discuss the currently ongoing efforts aimed to circumvent the chemo-resistance. We also highlight the new challenges, limitations and future directions for the development of improved therapeutic approaches such as fourth-generation EGFR-TKIs, peptides, nanobodies, PROTACs etc.Copyright © 2023. Published by Elsevier B.V.