Department of Pharmacology and Physiology, College of Medicine, Drexel University, USA; Cancer Biology Program and The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, USA.
Cancer Biology Program and The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, USA.
Biochem Pharmacol. 2018 Dec;158:217-228. doi: 10.1016/j.bcp.2018.10.022. Epub 2018 Oct 21.
RAS is the most commonly mutated driver of tumorigenesis, seen in about 30% of all cancer cases. There is a subset of tumors termed RAS-driven cancers in which RAS mutation or overactivation is evident, including as much as 95% in pancreatic and 50% in colon cancer. RAS is a family of small membrane bound GTPases that act as a signaling node to control both normal and cancer biology. Since the discovery of RAS' overall prominence in many tumor types and specifically in RAS-dependent cancers, it has been an obvious therapeutic target for drug development. However, RAS has proved a very elusive target, and after a few prominent RAS targeted drugs failed in clinical trials after decades of research, RAS was termed "undruggable" and research in this field was greatly hampered. An increase in knowledge about basic RAS biology has led to a resurgence in the generation of novel therapeutics targeting RAS signaling utilizing various and distinct approaches. These new drugs target RAS activation directly, block downstream signaling effectors and inhibit proper post-translational processing and trafficking/recycling of RAS. This review will cover how these new drugs were developed and how they have fared in preclinical and early phase clinical trials.
RAS 是最常见的肿瘤发生驱动因素突变，可见于约 30%的所有癌症病例中。有一部分被称为 RAS 驱动的肿瘤，其中 RAS 突变或过度激活明显，包括高达 95%的胰腺癌和 50%的结肠癌。RAS 是一个小的膜结合 GTPase 家族，作为一个信号节点，控制正常和癌症生物学。自从发现 RAS 在许多肿瘤类型中，特别是在 RAS 依赖性癌症中普遍存在以来，它一直是药物开发的一个明显的治疗靶点。然而，RAS 被证明是一个非常难以捉摸的靶点，经过几十年的研究，一些著名的 RAS 靶向药物在临床试验中失败后，RAS 被称为“不可成药”，该领域的研究受到了极大的阻碍。对 RAS 生物学基础知识的了解增加，导致利用各种不同的方法针对 RAS 信号产生新的治疗方法的重新兴起。这些新药直接针对 RAS 激活，阻断下游信号效应器，并抑制 RAS 的适当翻译后加工和运输/回收。这篇综述将介绍这些新药是如何开发的，以及它们在临床前和早期临床试验中的表现。
