Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY, USA; Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA.
Cell. 2020 Nov 12;183(4):850-859. doi: 10.1016/j.cell.2020.09.044. Epub 2020 Oct 15.
KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing 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 emerging 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 toward improving patient outcomes in the clinic.
KRAS 突变是肺癌、结直肠癌和胰腺癌中最常见的遗传改变之一。直接抑制 KRAS 癌蛋白一直是精准肿瘤学的长期追求，这一目标是在近 40 年前发现人类癌细胞中的 RAS 突变后不久确立的。近年来，药物化学的进展已经确立了针对 KRAS(G12C)的抑制剂，该突变存在于约 13%的肺腺癌中，在其他癌症中则以较低的频率存在。描述这些抑制剂的发现和作用机制的临床前研究，加上来自接受这些药物治疗的患者的新兴临床数据，激发了人们对 KRAS 及其治疗潜力的重新研究。在这里，我们讨论了这些进展如何重塑 KRAS 癌蛋白生物学的基本方面，以及在改善临床患者预后方面所取得的进展。
