Mayo Clinic, Rochester, USA.
Portsmouth University Hospitals NHS Trust, Portsmouth, UK.
J Hematol Oncol. 2022 Oct 25;15(1):152. doi: 10.1186/s13045-022-01375-4.
After decades of efforts, we have recently made progress into targeting KRAS mutations in several malignancies. Known as the 'holy grail' of targeted cancer therapies, KRAS is the most frequently mutated oncogene in human malignancies. Under normal conditions, KRAS shuttles between the GDP-bound 'off' state and the GTP-bound 'on' state. Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis. In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein. Covalent inhibitors that block mutant KRAS G12C were successfully developed and sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline. Simultaneously, effects of KRAS mutations on tumour microenvironment were also discovered, partly owing to the universal use of immune checkpoint inhibitors. In this review, we discuss the discovery, biology, and function of KRAS in human malignancies. We also discuss the relationship between KRAS mutations and the tumour microenvironment, and therapeutic strategies to target KRAS. Finally, we review the current clinical evidence and ongoing clinical trials of novel agents targeting KRAS and shine light on resistance pathways known so far.
经过几十年的努力，我们最近在几种恶性肿瘤中靶向 KRAS 突变方面取得了进展。KRAS 被称为靶向癌症治疗的“圣杯”，是人类恶性肿瘤中最常发生突变的致癌基因。在正常情况下，KRAS 在 GDP 结合的“关闭”状态和 GTP 结合的“开启”状态之间穿梭。突变的 KRAS 持续激活，并导致持续的下游信号转导和致癌作用。2013 年，对 KRAS 生物学的深入了解和新的药物设计技术导致了一个关键的发现，即在 GDP 结合的突变型 KRAS G12C 蛋白中存在一个半胱氨酸药物结合口袋。能够阻断突变型 KRAS G12C 的共价抑制剂被成功开发出来，索托拉西布是第一个被批准的 KRAS G12C 抑制剂，还有更多的抑制剂正在研发中。同时，KRAS 突变对肿瘤微环境的影响也被发现，部分原因是免疫检查点抑制剂的广泛使用。在这篇综述中，我们讨论了 KRAS 在人类恶性肿瘤中的发现、生物学和功能。我们还讨论了 KRAS 突变与肿瘤微环境的关系，以及针对 KRAS 的治疗策略。最后，我们回顾了目前针对 KRAS 的新型靶向药物的临床证据和正在进行的临床试验，并探讨了迄今为止已知的耐药途径。
