Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, UK; Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, London and Manchester, UK.
Cancer Research UK Lung Cancer Centre of Excellence, London and Manchester, UK; Department of Oncology, University College of London Hospital and UCL Cancer Institute, London, UK.
Eur J Cancer. 2018 Aug;99:20-27. doi: 10.1016/j.ejca.2018.05.001. Epub 2018 Jun 9.
Despite being the most frequent gain-of-function genetic alteration in human cancer, KRAS mutation has to date offered only limited potential as a prognostic and predictive biomarker. Results from the phase III SELECT-1 trial in non-small cell lung cancer (NSCLC) recently added to a number of historical and more contemporary disappointments in targeting KRAS mutant disease, including farnesyl transferase inhibition and synthetic lethality partners such as STK33. This narrative review uses the context of these previous failures to demonstrate how the knowledge gained from these experiences can be used as a platform for exciting advances in NSCLC on the horizon. It now seems clear that mutational subtype (most commonly G12C) of individual mutations is of greater relevance than the categorical evaluation of KRAS mutation presence or otherwise. A number of direct small molecules targeted to these subtypes are in development and have shown promising biological activity, with some in the late stages of preclinical validation.
尽管 KRAS 突变是人类癌症中最常见的功能获得性遗传改变，但迄今为止，它仅作为预后和预测生物标志物具有有限的潜力。最近，III 期 SELECT-1 试验在非小细胞肺癌（NSCLC）中的结果，加上针对 KRAS 突变疾病的许多历史和更现代的失望结果，包括法呢基转移酶抑制和合成致死性伙伴如 STK33，都为这一结果做出了贡献。本叙述性评论利用以前的失败经验来证明，从这些经验中获得的知识如何可以作为 NSCLC 领域令人兴奋的新进展的平台。现在看来，单个突变的突变亚型（最常见的是 G12C）比 KRAS 突变存在与否的分类评估更重要。目前正在开发针对这些亚型的许多直接小分子药物，并显示出有前途的生物学活性，其中一些已进入临床前验证的后期阶段。
