Du Yafei, Karatekin Feride, Wang Wendy Kehan, Hong Wanjin, Boopathy Gandhi T K
Cancer Signaling & Therapies, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A∗STAR), Proteos, Singapore, Singapore; Department of Chemistry, National University of Singapore, Singapore, Singapore.
Cancer Signaling & Therapies, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A∗STAR), Proteos, Singapore, Singapore.
Pharmacol Rev. 2025 Jun 25;77(5):100076. doi: 10.1016/j.pharmr.2025.100076.
Epidermal growth factor receptor (EGFR) plays a crucial role in tumorigenesis across multiple cancer types. EGFR mutations, overexpression, amplifications, dysregulated signaling, and impaired receptor downregulation drive cancer progression, particularly in non-small cell lung cancer, glioblastoma, colorectal cancer, gastric cancer, and head and neck cancers. Over the past decades, EGFR-targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, have significantly improved patient outcomes. However, drug resistance inevitably arises through on-target mutations, activation of bypass signaling pathways, and disruptions in receptor trafficking and degradation. To overcome resistance, novel therapeutic strategies such as new generation of tyrosine kinase inhibitors, antibody-drug conjugates, and targeted protein degradation approaches like proteolysis-targeting chimeras are being actively explored. Additionally, combination therapies targeting parallel or compensatory pathways are being explored in mitigating drug resistance. Advances in genomic profiling and liquid biopsy technologies further enable personalized treatment strategies tailored to individual genetic backgrounds. In this review, we provide an overview of EGFR signaling and examine the landscape of EGFR mutations and currently available targeted therapies, while highlighting key resistance mechanisms. Furthermore, emerging strategies designed to overcome resistance are discussed, offering insights into future directions for EGFR-targeted cancer treatment. SIGNIFICANCE STATEMENT: Epidermal growth factor receptor (EGFR) is a key driver of tumorigenesis across multiple cancers, with overexpression, mutations, and amplifications promoting disease progression and therapeutic resistance. Despite the success of EGFR-targeted therapies, resistance remains a significant barrier to sustainable efficacy. This review provides an overview of EGFR biology and therapy, resistance mechanisms, and emerging new therapeutic strategies. A deeper understanding of these aspects is crucial for overcoming resistance and guiding the development of more effective and personalized cancer treatments.
表皮生长因子受体（EGFR）在多种癌症类型的肿瘤发生过程中起着关键作用。EGFR突变、过表达、扩增、信号失调以及受体下调受损会推动癌症进展，尤其是在非小细胞肺癌、胶质母细胞瘤、结直肠癌、胃癌和头颈癌中。在过去几十年中，包括酪氨酸激酶抑制剂和单克隆抗体在内的EGFR靶向疗法显著改善了患者的治疗效果。然而，通过靶点突变、旁路信号通路激活以及受体转运和降解的破坏，不可避免地会产生耐药性。为了克服耐药性，人们正在积极探索新一代酪氨酸激酶抑制剂、抗体药物偶联物以及蛋白酶靶向嵌合体等靶向蛋白降解方法等新型治疗策略。此外，正在探索针对平行或补偿通路的联合疗法以减轻耐药性。基因组分析和液体活检技术的进展进一步使根据个体遗传背景量身定制个性化治疗策略成为可能。在本综述中，我们概述了EGFR信号传导，研究了EGFR突变情况和目前可用的靶向疗法，同时强调了关键的耐药机制。此外，还讨论了旨在克服耐药性的新兴策略，为EGFR靶向癌症治疗的未来方向提供了见解。意义声明：表皮生长因子受体（EGFR）是多种癌症肿瘤发生的关键驱动因素，其过表达、突变和扩增促进疾病进展和治疗耐药性。尽管EGFR靶向疗法取得了成功，但耐药性仍然是可持续疗效的重大障碍。本综述概述了EGFR生物学和治疗、耐药机制以及新兴的新治疗策略。对这些方面的更深入理解对于克服耐药性和指导开发更有效、个性化的癌症治疗方法至关重要。
