Targeting Epidermal Growth Factor Receptor for Cancer Treatment: Abolishing Both Kinase-Dependent and Kinase-Independent Functions of the Receptor.
Targeting Epidermal Growth Factor Receptor for Cancer Treatment: Abolishing Both Kinase-Dependent and Kinase-Independent Functions of the Receptor.
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DOI：
10.1124/pharmrev.123.000906
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发表时间：
2023-11
影响因子：
21.1
通讯作者：
中科院分区：
文献类型：
--
作者：
表皮生长因子受体（EGFR）是一种酪氨酸激酶受体，可通过配体结合、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的致癌活性。大量的EGFR抑制剂已被开发用于癌症治疗，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酪氨酸激酶的激活或活性。然而，这些药物仅对少数几种癌症有效。耐药性，无论是内在的还是获得性的，即使在抑制剂已经显示出疗效的癌症中也很常见。耐药机制复杂，尚不完全清楚。癌细胞对EGFR抑制剂具有耐药性的关键易感性尚未被确定。然而，近年来人们越来越认识到EGFR也具有激酶无关的致癌功能，这些非规范功能可能在肿瘤对EGFR抑制剂的耐药中发挥关键作用。本文综述了EGFR的激酶依赖性和非依赖性活性。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过表达和EGFR与其他受体酪氨酸激酶相互作用以对抗EGFR抑制剂。此外，本综述讨论了在临床前研究中显示出克服当前EGFR抑制剂局限性潜力的新兴实验性治疗方法。这些发现强调了靶向EGFR激酶依赖性和非依赖性功能以提高治疗效果和减少耐药性的重要性和可行性。EGFR是一个主要的致癌驱动因素和治疗靶点，但目前的EGFR抑制剂对癌症的耐药性仍然是一个重要的未满足的临床问题。本文综述了EGFR的肿瘤生物学，以及目前和新出现的EGFR抑制剂的作用机制和治疗效果。这一发现可能会导致对egfr阳性癌症更有效的治疗方法的开发。
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. 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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影响因子：
3.7
作者：
Tabara K;Kanda R;Sonoda K;Kubo T;Murakami Y;Kawahara A;Azuma K;Abe H;Kage M;Yoshinaga A;Tahira T;Hayashi K;Arao T;Nishio K;Rosell R;Kuwano M;Ono M
通讯作者：
Ono M
影响因子：
8.8
作者：
Rego, R. L.;Foster, N. R.;Smyrk, T. C.;Le, M.;O'Connell, M. J.;Sargent, D. J.;Windschitl, H.;Sinicrope, F. A.
通讯作者：
Sinicrope, F. A.
影响因子：
5
作者：
Byeon, Sun-ju;Lee, Hye Seung;Kim, Woo Ho
通讯作者：
Kim, Woo Ho
DOI：
10.1007/978-3-319-96704-2_9
发表时间：
2018-01-01
期刊：
ENDOCYTOSIS AND SIGNALING
影响因子：
--
作者：
Caldieri, Giusi;Malabarba, Maria Grazia;Sigismund, Sara
通讯作者：
Sigismund, Sara
影响因子：
64.8
作者：
CARPENTER, G;KING, L;COHEN, S
通讯作者：
COHEN, S