Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is activated by ligand binding, overexpression, or mutation. It is well known for its tyrosine kinase-dependent oncogenic activities in a variety of human cancers. A large number of EGFR inhibitors have been developed for cancer treatment, including monoclonal antibodies, tyrosine kinase inhibitors, and a vaccine. The EGFR inhibitors are aimed at inhibiting the activation or the activity of EGFR tyrosine kinase. However, these agents have shown efficacy in only a few types of cancers. Drug resistance, both intrinsic and acquired, is common even in cancers where the inhibitors have shown efficacy. The drug resistance mechanism is complex and not fully known. The key vulnerability of cancer cells that are resistant to EGFR inhibitors has not been identified. Nevertheless, it has been increasingly recognized in recent years that EGFR also possesses kinase-independent oncogenic functions and that these noncanonical functions may play a crucial role in cancer resistance to EGFR inhibitors. In this review, both kinase-dependent and -independent activities of EGFR are discussed. Also discussed are the mechanisms of actions and therapeutic activities of clinically used EGFR inhibitors and sustained EGFR overexpression and EGFR interaction with other receptor tyrosine kinases to counter the EGFR inhibitors. Moreover, this review discusses emerging experimental therapeutics that have shown potential for overcoming the limitation of the current EGFR inhibitors in preclinical studies. The findings underscore the importance and feasibility of targeting both kinase-dependent and -independent functions of EGFR to enhance therapeutic efficacy and minimize drug resistance.

中文翻译：

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靶向表皮生长因子受体进行癌症治疗：消除受体的激酶依赖性和激酶非依赖性功能

表皮生长因子受体 (EGFR) 是一种受体酪氨酸激酶，通过配体结合、过度表达或突变而被激活。它以其在多种人类癌症中的酪氨酸激酶依赖性致癌活性而闻名。目前已开发出大量用于癌症治疗的 EGFR 抑制剂，包括单克隆抗体、酪氨酸激酶抑制剂和疫苗。EGFR抑制剂旨在抑制EGFR酪氨酸激酶的活化或活性。然而，这些药物仅对少数类型的癌症显示出疗效。即使在抑制剂已显示出疗效的癌症中，内在的和获得性的耐药性也很常见。耐药机制复杂且尚不完全清楚。对 EGFR 抑制剂耐药的癌细胞的关键脆弱性尚未确定。然而，近年来人们越来越认识到EGFR还具有激酶独立的致癌功能，并且这些非经典功能可能在癌症对EGFR抑制剂的耐药性中发挥着至关重要的作用。在这篇综述中，讨论了 EGFR 的激酶依赖性和非激酶依赖性活性。还讨论了临床使用的 EGFR 抑制剂的作用机制和治疗活性，以及​​持续的 EGFR 过表达以及 EGFR 与其他受体酪氨酸激酶的相互作用以对抗 EGFR 抑制剂。此外，本综述讨论了新兴的实验疗法，这些疗法在临床前研究中显示出克服当前 EGFR 抑制剂局限性的潜力。这些发现强调了靶向 EGFR 的激酶依赖性和非激酶依赖性功能以增强治疗效果并最大限度地减少耐药性的重要性和可行性。