Madhunapantula SubbaRao V, Robertson Gavin P
Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Cancer Res. 2008 Jan 1;68(1):5-8. doi: 10.1158/0008-5472.CAN-07-2038.
The RAF family members, A-Raf, B-Raf, and C-Raf (or Raf-1), are intermediate molecules in the mitogen-activated protein (MAP) kinase [Ras/Raf/MAP kinase/extracellular signal-regulated kinase (Erk) kinase (MEK)/Erk] pathway, which relays extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events ultimately promoting cancer development. This pathway is activated by mutation in approximately 7% of all human cancers. B-Raf is one of the proteins frequently mutated to an active form during tumor development. Therefore, B-Raf is an attractive cancer target but lack of clinical efficacy using agents targeting this protein has raised serious doubts about its therapeutic utility. Design of more effective B-Raf inhibitory agents, targeting other members of the signaling cascade for greater clinical efficacy or inhibiting B-Raf in combination with other targets, is being evaluated to resolve these perplexing issues. Here, we discuss recent progress, using preclinical models and clinical studies, to resolve the controversy of whether B-Raf would be a good therapeutic target for melanoma and other malignancies.
RAF家族成员，即A-Raf、B-Raf和C-Raf（或Raf-1），是丝裂原活化蛋白（MAP）激酶[Ras/Raf/MAP激酶/细胞外信号调节激酶（Erk）激酶（MEK）/Erk]信号通路中的中间分子，该信号通路通过一系列磷酸化事件将细胞外信号从细胞膜传递至细胞核，最终促进癌症发展。在所有人类癌症中，约7%的癌症是由该信号通路的突变激活的。B-Raf是肿瘤发生过程中经常突变为活性形式的蛋白之一。因此，B-Raf是一个有吸引力的癌症靶点，但使用靶向该蛋白的药物缺乏临床疗效，这引发了人们对其治疗效用的严重质疑。为了解决这些棘手问题，目前正在评估设计更有效的B-Raf抑制剂，这些抑制剂靶向信号级联反应的其他成员以提高临床疗效，或与其他靶点联合抑制B-Raf。在此，我们利用临床前模型和临床研究，讨论在解决B-Raf是否是黑色素瘤和其他恶性肿瘤的良好治疗靶点这一争议方面取得的最新进展。
