Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.
James Thoracic Oncology Center, The Ohio State University, Columbus, USA.
Ann Oncol. 2021 Sep;32(9):1101-1110. doi: 10.1016/j.annonc.2021.06.001. Epub 2021 Jun 2.
Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs). While the use of targeted therapies and immune checkpoint inhibitors (CPIs) has drastically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC) in recent years, historic attempts to target KRAS (both direct and indirect approaches) have had little success, and no KRAS-specific targeted therapies have been approved to date for patients in this molecular subset of NSCLC. With the discovery by Ostrem, Shokat, and colleagues of the switch II pocket on the surface of the active and inactive forms of KRAS, we now have an improved understanding of the complex interactions involved in the RAS family of signaling proteins which has led to the development of a number of promising direct KRAS inhibitors, such as sotorasib and adagrasib. In previously treated patients with KRAS-mutant NSCLC, clinical activity has been shown for both sotorasib and adagrasib monotherapy; these data suggest promising new treatment options are on the horizon. With the stage now set for a new era in the treatment of KRAS-mutated NSCLC, many questions remain to be answered in order to further elucidate the mechanisms of resistance, how best to use combination strategies, and if KRAS inhibitors will have suitable activity in earlier lines of therapy for patients with advanced/metastatic NSCLC.
鼠肉瘤（RAS）是人类癌症中最常发生突变的癌基因，其中 Kirsten 鼠肉瘤（KRAS）是最常发生突变的 RAS 同工型。总体而言，KRAS 占人类癌症中观察到的 RAS 突变的 85%，并且存在于 35%的肺腺癌（LUAD）中。尽管近年来靶向治疗和免疫检查点抑制剂（CPIs）的使用极大地改变了晚期非小细胞肺癌（NSCLC）的治疗格局，但历史上靶向 KRAS（直接和间接方法）的尝试收效甚微，并且迄今为止，没有针对这一 NSCLC 分子亚组的 KRAS 特异性靶向治疗方法获得批准。随着 Ostrem、Shokat 和同事们发现 KRAS 的活性和非活性形式表面的开关 II 口袋，我们现在对 RAS 家族信号蛋白的复杂相互作用有了更好的理解，这导致了许多有前途的直接 KRAS 抑制剂的开发，例如 sotorasib 和 adagrasib。在 KRAS 突变型 NSCLC 的先前治疗患者中，sotorasib 和 adagrasib 单药治疗均显示出临床活性；这些数据表明有前途的新治疗选择即将出现。随着现在为治疗 KRAS 突变型 NSCLC 开辟了一个新时代，为了进一步阐明耐药机制、如何最好地使用联合策略，以及 KRAS 抑制剂是否会在晚期/转移性 NSCLC 患者的早期治疗线中具有适当的活性，仍有许多问题需要回答。
