Beeram Muralidhar, Patnaik Amita, Rowinsky Eric K
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
J Clin Oncol. 2005 Sep 20;23(27):6771-90. doi: 10.1200/JCO.2005.08.036.
The mitogen-activated protein kinase (MAPK) signaling pathway plays a critical role in transmitting proliferative signals generated by cell surface receptors and cytoplasmic signaling elements to the nucleus. Several important signaling elements of the MAPK pathway, particularly Ras and Raf, are encoded by oncogenes, and as such, their structures and functions can be modified, rendering them constitutively active. Because the MAPK pathway is dysregulated in a notable proportion of human malignancies, many of its aberrant and critical components represent strategic targets for therapeutic development against cancer. Raf, which is an essential serine/threonine kinase constituent of the MAPK pathway and a downstream effector of the central signal transduction mediator Ras, is activated in a wide range of human malignancies by aberrant signaling upstream of the protein (eg, growth factor receptors and mutant Ras) and activating mutations of the protein itself, both of which confer a proliferative advantage. Three isoforms of Raf have been identified, and therapeutics targeting Raf, including small-molecule inhibitors and antisense oligodeoxyribonucleotides (ASON), are undergoing clinical evaluation. The outcomes of these investigations may have far-reaching implications in the management of many types of human cancer. This review outlines the structure and diverse functions of Raf, the rationale for targeting Raf as a therapeutic strategy against cancer, and the present status of various therapeutic approaches including ASONs and small molecules, particularly sorafenib (BAY 43-9006).
丝裂原活化蛋白激酶（MAPK）信号通路在将细胞表面受体和细胞质信号元件产生的增殖信号传递至细胞核的过程中发挥着关键作用。MAPK通路的几个重要信号元件，尤其是Ras和Raf，由癌基因编码，因此，它们的结构和功能可能会发生改变，使其处于组成性激活状态。由于MAPK通路在相当一部分人类恶性肿瘤中失调，其许多异常且关键的组分成为了抗癌治疗研发的战略靶点。Raf是MAPK通路中一种必需的丝氨酸/苏氨酸激酶组分，也是中心信号转导介质Ras的下游效应器，在多种人类恶性肿瘤中，通过该蛋白上游的异常信号传导（如生长因子受体和突变型Ras）以及该蛋白本身的激活突变而被激活，这两者均赋予了增殖优势。已鉴定出Raf的三种同工型，针对Raf的治疗药物，包括小分子抑制剂和反义寡脱氧核糖核苷酸（ASON），正在进行临床评估。这些研究结果可能对多种类型人类癌症的治疗产生深远影响。本综述概述了Raf的结构和多种功能、将Raf作为抗癌治疗策略的基本原理，以及包括ASON和小分子（特别是索拉非尼，BAY 43 - 9006）在内的各种治疗方法的现状。
