Yan Chao, Theodorescu Dan
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China (C.Y.); Departments of Surgery (Urology) and Pharmacology, University of Colorado, Aurora, Colorado (D.T.); and University of Colorado Comprehensive Cancer Center, Aurora, Colorado (D.T.).
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China (C.Y.); Departments of Surgery (Urology) and Pharmacology, University of Colorado, Aurora, Colorado (D.T.); and University of Colorado Comprehensive Cancer Center, Aurora, Colorado (D.T.)
Pharmacol Rev. 2018 Jan;70(1):1-11. doi: 10.1124/pr.117.014415.
More than a hundred proteins comprise the RAS superfamily of small GTPases. This family can be divided into RAS, RHO, RAB, RAN, ARF, and RAD subfamilies, with each shown to play distinct roles in human cells in both health and disease. The RAS subfamily has a well-established role in human cancer with the three genes, , , and being the commonly mutated in tumors. These mutations, most often functionally activating, are especially common in pancreatic, lung, and colorectal cancers. Efforts to inhibit RAS and related GTPases have produced inhibitors targeting the downstream effectors of RAS signaling, including inhibitors of the RAF-mitogen-activated protein kinase/extracellular signal-related kinase (ERK)-ERK kinase pathway and the phosphoinositide-3-kinase-AKT-mTOR kinase pathway. A third effector arm of RAS signaling, mediated by RAL (RAS like) has emerged in recent years as a critical driver of RAS oncogenic signaling and has not been targeted until recently. RAL belongs to the RAS branch of the RAS superfamily and shares a high structural similarity with RAS. In human cells, there are two genes, and , both of which have been shown to play roles in the proliferation, survival, and metastasis of a variety of human cancers, including lung, colon, pancreatic, prostate, skin, and bladder cancers. In this review, we summarize the latest knowledge of RAL in the context of human cancer and the recent advancements in the development of cancer therapeutics targeting RAL small GTPases.
一百多种蛋白质构成了小GTP酶的RAS超家族。这个家族可分为RAS、RHO、RAB、RAN、ARF和RAD亚家族，每个亚家族在人类细胞的健康和疾病状态中都发挥着不同的作用。RAS亚家族在人类癌症中具有明确的作用，其中三个基因（KRAS、NRAS和BRAF）在肿瘤中常见突变。这些突变大多在功能上具有激活作用，在胰腺癌、肺癌和结直肠癌中尤为常见。抑制RAS及相关GTP酶的努力产生了针对RAS信号下游效应器的抑制剂，包括RAF-丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK）-ERK激酶途径抑制剂和磷酸肌醇-3-激酶-AKT-雷帕霉素靶蛋白激酶途径抑制剂。近年来，由RAL（RAS样蛋白）介导的RAS信号的第三条效应臂已成为RAS致癌信号的关键驱动因素，直到最近才成为靶点。RAL属于RAS超家族的RAS分支，与RAS具有高度的结构相似性。在人类细胞中，有两个基因（RALGDS和RALBP1），它们在包括肺癌、结肠癌、胰腺癌、前列腺癌、皮肤癌和膀胱癌在内的多种人类癌症的增殖、存活和转移中都发挥了作用。在这篇综述中，我们总结了RAL在人类癌症背景下的最新知识以及靶向RAL小GTP酶的癌症治疗方法的最新进展。
