Department of Pediatrics, University of California, San Francisco, USA.
Blood. 2012 Oct 25;120(17):3397-406. doi: 10.1182/blood-2012-05-378596. Epub 2012 Aug 16.
Ras proteins are critical nodes in cellular signaling that integrate inputs from activated cell surface receptors and other stimuli to modulate cell fate through a complex network of effector pathways. Oncogenic RAS mutations are found in ∼25% of human cancers and are highly prevalent in hematopoietic malignancies. Because of their structural and biochemical properties, oncogenic Ras proteins are exceedingly difficult targets for rational drug discovery, and no mechanism-based therapies exist for cancers with RAS mutations. This article reviews the properties of normal and oncogenic Ras proteins, the prevalence and likely pathogenic role of NRAS, KRAS, and NF1 mutations in hematopoietic malignancies, relevant animal models of these cancers, and implications for drug discovery. Because hematologic malignancies are experimentally tractable, they are especially valuable platforms for addressing the fundamental question of how to reverse the adverse biochemical output of oncogenic Ras in cancer.
Ras 蛋白是细胞信号转导中的关键节点，它整合来自激活的细胞表面受体和其他刺激的输入，通过复杂的效应途径网络来调节细胞命运。致癌 Ras 突变存在于约 25%的人类癌症中，在血液恶性肿瘤中非常普遍。由于其结构和生化特性，致癌 Ras 蛋白是合理药物发现的极难靶点，并且没有针对 Ras 突变癌症的基于机制的治疗方法。本文综述了正常和致癌 Ras 蛋白的特性、NRAS、KRAS 和 NF1 突变在血液恶性肿瘤中的流行程度和可能的致病作用、这些癌症的相关动物模型，以及对药物发现的影响。由于血液恶性肿瘤具有可实验性，因此它们是解决如何逆转癌症中致癌 Ras 不良生化输出这一基本问题的特别有价值的平台。
