Targeting Epidermal Growth Factor Receptor for Cancer Treatment: Abolishing Both Kinase-Dependent and Kinase-Independent Functions of the Receptor.

IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmacological Reviews Pub Date : 2023-11-01 Epub Date: 2023-06-20 DOI:10.1124/pharmrev.123.000906
Yuesheng Zhang
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Abstract

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. SIGNIFICANCE STATEMENT: EGFR is a major oncogenic driver and therapeutic target, but cancer resistance to current EGFR inhibitors remains a significant unmet clinical problem. This article reviews the cancer biology of EGFR as well as the mechanisms of actions and the therapeutic efficacies of current and emerging EGFR inhibitors. The findings could potentially lead to development of more effective treatments for EGFR-positive cancers.

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靶向表皮生长因子受体治疗癌症: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、过表达或突变激活。众所周知,它在多种人类癌症中具有酪氨酸激酶依赖性致癌活性。已经开发了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,这些药物仅在少数类型的癌症中显示出疗效。耐药性,包括内在耐药性和获得性耐药性,即使在抑制剂显示出疗效的癌症中也很常见。耐药性机制复杂,尚不完全清楚。癌症细胞对EGFR抑制剂具有耐药性的关键脆弱性尚未确定。然而,近年来人们越来越认识到,EGFR也具有激酶依赖性致癌功能,这些非致癌功能可能在癌症对EGFR抑制剂的耐药性中发挥关键作用。在这篇综述中,EGFR的激酶依赖性和非依赖性活性都进行了讨论。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过表达和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,这篇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激酶依赖性和非依赖性功能的重要性和可行性,以提高疗效并最大限度地减少耐药性。意义声明:EGFR是一个主要的致癌驱动因素和治疗靶点,但癌症对目前EGFR抑制剂的耐药性仍然是一个尚未解决的重大临床问题。本文综述了EGFR的癌症生物学,以及目前和新出现的EGFR抑制剂的作用机制和疗效。这些发现可能会为EGFR阳性癌症开发更有效的治疗方法。
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来源期刊
Pharmacological Reviews
Pharmacological Reviews 医学-药学
CiteScore
34.70
自引率
0.50%
发文量
40
期刊介绍: Pharmacological Reviews is a highly popular and well-received journal that has a long and rich history of success. It was first published in 1949 and is currently published bimonthly online by the American Society for Pharmacology and Experimental Therapeutics. The journal is indexed or abstracted by various databases, including Biological Abstracts, BIOSIS Previews Database, Biosciences Information Service, Current Contents/Life Sciences, EMBASE/Excerpta Medica, Index Medicus, Index to Scientific Reviews, Medical Documentation Service, Reference Update, Research Alerts, Science Citation Index, and SciSearch. Pharmacological Reviews offers comprehensive reviews of new pharmacological fields and is able to stay up-to-date with published content. Overall, it is highly regarded by scholars.
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