Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients.
Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients.
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DOI：
10.1016/j.cell.2020.09.044
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发表时间：
2020-11-12
期刊：
影响因子：
64.5
通讯作者：
Lito P
中科院分区：
文献类型：
--
作者：
Kim D;Xue JY;Lito P
KRAS突变是肺癌、结直肠癌和胰腺癌中最常见的基因变化之一。直接抑制KRAS癌蛋白一直是精密肿瘤学的长期追求，近40年前在人类癌细胞中发现RAS突变后不久就建立了这一目标。药物化学的最新进展已经建立了针对KRAS(G12C)的抑制剂，KRAS(G12C)是一种突变，在约13%的肺腺癌中发现，在其他癌症中的频率较低。描述它们的发现和作用机制的临床前研究，加上使用这些药物治疗的患者的早期临床数据，重新激发了人们对KRAS及其治疗潜力的研究热情。在这里，我们讨论这些进展如何重塑KRAS癌蛋白生物学的基本方面，以及在临床改善患者预后方面取得的进展。
KRAS mutations are among the most common genetic alterations in lung, colorectal and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a longstanding pursuit in precision oncology, one established shortly after the discovery of RAS mutations in human cancer cells nearly 40 years ago. Recent advances in medicinal chemistry have established inhibitors targeting KRAS(G12C), a mutation found in ~13% of lung adenocarcinomas and, at a lower frequency, in other cancers. Preclinical studies describing their discovery and mechanism of action, coupled with early clinical data from patients treated with these drugs, have sparked a renewed enthusiasm in the study of KRAS and its therapeutic potential. Here we discuss how these advances are reshaping the fundamental aspects of KRAS oncoprotein biology and the strides being made towards improving patient outcomes in the clinic.