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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02903-0

摘要内容如下：

RAS家族变异体（其中大多数涉及KRAS）是人类癌症中最常见的热点突变，与预后不良相关。近四十年来，KRAS一直被认为是不可用药的，部分原因是它的结构缺乏小分子结合位点。但生物工程、有机化学和相关领域的最新发展提供了基础设施，使直接KRAS靶向成为可能。在非小细胞肺癌中，KRAS P.Gly12Cys（G12C）的等位基因特异性靶向首次取得成功，导致两种药物Sotorasib和Adagrasib获得监管批准。针对G12C以外的其他变体的抑制剂在高度难治性恶性肿瘤（如胰腺癌）中显示出初步的抗肿瘤活性。在此，我们概述了以KRAS为重点的RAS病理学，说明了各种恶性肿瘤的治疗方法，包括强调“开”和“关”开关等位基因特异性和“泛” RAS抑制剂，并回顾了免疫治疗和其他关键组合RAS靶向策略。我们总结了对新的和获得性耐药的机制理解，回顾了联合方法、新兴技术和药物开发模式，并概述了KRAS疗法的未来蓝图，预计将产生深远的临床影响。

英文原文如下：

Abstracts

RAS family variants-most of which involve KRAS-are the most commonly occurring hotspot mutations in human cancers and are associated with a poor prognosis. For almost four decades, KRAS has been considered undruggable, in part due to its structure, which lacks small-molecule binding sites. But recent developments in bioengineering, organic chemistry and related fields have provided the infrastructure to make direct KRAS targeting possible. The first successes occurred with allele-specific targeting of KRAS p.Gly12Cys (G12C) in non-small cell lung cancer, resulting in regulatory approval of two agents-sotorasib and adagrasib. Inhibitors targeting other variants beyond G12C have shown preliminary antitumor activity in highly refractory malignancies such as pancreatic cancer. Herein, we outline RAS pathobiology with a focus on KRAS, illustrate therapeutic approaches across a variety of malignancies, including emphasis on the 'on' and 'off' switch allele-specific and 'pan' RAS inhibitors, and review immunotherapeutic and other key combination RAS targeting strategies. We summarize mechanistic understanding of de novo and acquired resistance, review combination approaches, emerging technologies and drug development paradigms and outline a blueprint for the future of KRAS therapeutics with anticipated profound clinical impact.

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