Blocking Oncogenic Ras Signaling for Cancer Therapy

Abstract

The Ras gene product is a monomeric membrane-localized G protein of 21 kd that functions as a molecular switch linking receptor and nonreceptor tyrosine kinase activation to downstream cytoplasmic or nuclear events. Each mammalian cell contains at least three distinct ras proto-oncogenes encoding closely related, but distinct proteins. Activating mutations in these Ras proteins result in constitutive signaling, thereby stimulating cell proliferation and inhibiting apoptosis. Oncogenic mutations in the ras gene are present in approximately 30% of all human cancers. K-ras mutations occur frequently in non-small-cell lung, colorectal, and pancreatic carcinomas; H-ras mutations are common in bladder, kidney, and thyroid carcinomas; N-ras mutations are found in melanoma, hepatocellular carcinoma, and hematologic malignancies. The ras-signaling pathway has attracted considerable attention as a target for anticancer therapy because of its important role in carcinogenesis. In this review, the physiologic and biochemical properties of the Ras proteins, their mechanism of cell signaling, and their relation to human cancer will be discussed. Novel cancer therapeutic approaches based on the inhibition of Ras-mediated signaling, including inhibition of Ras processing, inhibition of Ras protein synthesis, and blockage of downstream Ras effectors, will be discussed. [J Natl Cancer Inst 2001;93:1062-74] Cell proliferation, differentiation, and survival are regulated by a number of extracellular hormones, growth factors, and cytokines in complex organisms. These molecules serve as ligands for cellular receptors and communicate with the nucleus of the cell through a network of intracellular signaling pathways. In cancer cells, dysregulated cell signaling and proliferation may occur through overexpression or mutation of proto-oncogenes. One such proto-oncogene is ras, which functions as a molecular switch in a large network of signaling pathways, mainly controlling the differentiation or proliferation of cells. Mutated ras genes encode constitutively activated proteins, which have been implicated in tumorigenesis. Mutations in ras have been identified in approximately 30% of all human cancers, making this G protein an important target for the development of anticancer drugs.