Abstract：
The RAS oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in the KRAS gene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring the KRASG12C mutation. Adagrasib (MRTX849) and other direct KRASG12C inhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRASG12C mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRASG12C inhibitors and summarize the ongoing clinical trials of all direct KRASG12C inhibitors.
摘要：
RAS癌基因既是人类癌症中最常见的突变癌基因，也是1982年发现的第一个确认的人类癌基因。经过几十年的研究,2013年，Shokat实验室取得了开创性的突破，表明可以通过新发现的开关II口袋直接抑制由KRAS基因中的G12C突变引起的活化的KRAS同工酶。在这一开创性发现的基础上，索托拉西（AMG510）于2021年获得美国食品和药物管理局的批准，成为第一个在任何KRAS突变癌症中直接靶向KRAS癌蛋白的疗法，特别是那些有KRASG12C突变的。Adagrasib（MRTX849）和其他直接KRASG12C抑制剂目前正在多个临床试验中进行研究。在这次审查中,我们深入研究了这种新型KRAS抑制剂的开发路径，从发现开始，结构,和RAS家族癌蛋白的功能。然后我们检查KRAS的临床相关性，特别是人类癌症中的KRASG12C突变，通过对其癌症流行病学进行深入分析。最后,我们回顾了支持KRASG12C直接抑制剂初步开发的临床前证据,并总结了所有KRASG12C直接抑制剂正在进行的临床试验.
