Healy Fiona M, Prior Ian A, MacEwan David J
Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK.
Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK.
Br J Pharmacol. 2022 Jun;179(12):2844-2867. doi: 10.1111/bph.15420. Epub 2021 Apr 6.
In this review, we analyse the impact of oncogenic Ras mutations in mediating cancer drug resistance and the progress made in the abrogation of this resistance, through pharmacological targeting. At a physiological level, Ras is implicated in many cellular proliferation and survival pathways. However, mutations within this small GTPase can be responsible for the initiation of cancer, therapeutic resistance and failure, and ultimately disease relapse. Often termed "undruggable," Ras is notoriously difficult to target directly, due to its structure and intrinsic activity. Thus, Ras-mediated drug resistance remains a considerable pharmacological problem. However, with advances in both analytical techniques and novel drug classes, the therapeutic landscape against Ras is changing. Allele-specific, direct Ras-targeting agents have reached clinical trials for the first time, indicating there may, at last, be hope of targeting such an elusive but significant protein for better more effective cancer therapy. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.
在本综述中，我们分析了致癌性Ras突变在介导癌症耐药性方面的影响，以及通过药理学靶向作用在消除这种耐药性方面所取得的进展。在生理水平上，Ras参与许多细胞增殖和存活途径。然而，这种小GTP酶内的突变可能导致癌症的发生、治疗耐药性和治疗失败，并最终导致疾病复发。由于其结构和内在活性，Ras通常被称为“不可成药的”，直接靶向它非常困难。因此，Ras介导的耐药性仍然是一个相当大的药理学问题。然而，随着分析技术和新型药物类别的进步，针对Ras的治疗前景正在发生变化。等位基因特异性、直接靶向Ras的药物首次进入临床试验，这表明最终可能有希望靶向这样一种难以捉摸但又非常重要的蛋白质，以实现更好、更有效的癌症治疗。相关文章：本文是关于癌症预防和治疗新途径（《英国药理学杂志》75周年）主题特刊的一部分。要查看本节中的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc。
