Baker Nicole M, Yee Chow Hoi, Chernoff Jonathan, Der Channing J
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Clin Cancer Res. 2014 Sep 15;20(18):4740-6. doi: 10.1158/1078-0432.CCR-13-1727.
Cancers driven by oncogenic Ras proteins encompass some of the most deadly human cancer types, and there is a pressing need to develop therapies for these diseases. Although recent studies suggest that mutant Ras proteins may yet be druggable, the most promising and advanced efforts involve inhibitors of Ras effector signaling. Most efforts to target Ras signaling have been aimed at the ERK mitogen-activated protein kinase and the phosphoinositide 3-kinase signaling networks. However, to date, no inhibitors of these Ras effector pathways have been effective against RAS-mutant cancers. This ineffectiveness is due, in part, to the involvement of additional effectors in Ras-dependent cancer growth, such as the Rac small GTPase and the p21-activated serine-threonine kinases (PAK). PAK proteins are involved in many survival, cell motility, and proliferative pathways in the cell and may present a viable new target in Ras-driven cancers. In this review, we address the role and therapeutic potential of Rac and group I PAK proteins in driving mutant Ras cancers.
由致癌性Ras蛋白驱动的癌症包含了一些最致命的人类癌症类型，因此迫切需要开发针对这些疾病的疗法。尽管最近的研究表明突变型Ras蛋白可能仍然是可成药的，但最有前景和最先进的研究方向是Ras效应器信号传导的抑制剂。大多数针对Ras信号传导的研究都集中在ERK丝裂原活化蛋白激酶和磷酸肌醇3激酶信号网络上。然而，迄今为止，这些Ras效应器途径的抑制剂对RAS突变型癌症均无效。这种无效性部分归因于其他效应器参与了Ras依赖性癌症的生长，例如Rac小GTP酶和p21活化的丝氨酸 - 苏氨酸激酶（PAK）。PAK蛋白参与细胞内许多生存、细胞运动和增殖途径，可能是Ras驱动癌症中一个可行的新靶点。在这篇综述中，我们探讨了Rac和I型PAK蛋白在驱动突变型Ras癌症中的作用及治疗潜力。
