Neel Nicole F, Martin Timothy D, Stratford Jeran K, Zand Tanya P, Reiner David J, Der Channing J
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Genes Cancer. 2011 Mar;2(3):275-87. doi: 10.1177/1947601911407329.
The high frequency of RAS mutations in human cancers (33%) has stimulated intense interest in the development of anti-Ras inhibitors for cancer therapy. Currently, the major focus of these efforts is centered on inhibitors of components involved in Ras downstream effector signaling. In particular, more than 40 inhibitors of the Raf-MEK-ERK mitogen-activated protein kinase cascade and phosphoinositide 3-kinase-AKT-mTOR effector signaling networks are currently under clinical evaluation. However, these efforts are complicated by the fact that Ras can utilize at least 9 additional functionally distinct effectors, with at least 3 additional effectors with validated roles in Ras-mediated oncogenesis. Of these, the guanine nucleotide exchange factors of the Ras-like (Ral) small GTPases (RalGEFs) have emerged as important effectors of mutant Ras in pancreatic, colon, and other cancers. In this review, we summarize the evidence for the importance of this effector pathway in cancer and discuss possible directions for therapeutic inhibition of aberrant Ral activation and signaling.
人类癌症中RAS突变的高频率（33%）激发了人们对开发用于癌症治疗的抗RAS抑制剂的浓厚兴趣。目前，这些努力的主要重点集中在Ras下游效应信号传导相关成分的抑制剂上。特别是，目前有40多种Raf-MEK-ERK丝裂原活化蛋白激酶级联反应和磷酸肌醇3激酶-AKT-mTOR效应信号网络的抑制剂正在进行临床评估。然而，这些努力因以下事实而变得复杂：Ras可以利用至少9种其他功能不同的效应器，其中至少3种效应器在Ras介导的肿瘤发生中具有已证实的作用。其中，Ras样（Ral）小GTP酶的鸟嘌呤核苷酸交换因子（RalGEFs）已成为胰腺、结肠和其他癌症中突变Ras的重要效应器。在这篇综述中，我们总结了这一效应器途径在癌症中的重要性的证据，并讨论了治疗性抑制异常Ral激活和信号传导的可能方向。
