Signaling Pathways Downstream of Rtks: Ras and PI3K Several oncogene and tumor-suppressor gene products are components of signal transduction pathways that emanate from RTK activation (Fig. 80-2). The most extensively studied are the Ras/mitogen-activated protein (MAP) kinase pathway and the phosphatidylinositol-3-kinase (PI3K) pathway, both of which regulate multiple processes in cancer cells, including cell cycle progression, resistance to apoptotic signals, angiogenesis, and cell motility. The development of inhibitors of these pathways is an important avenue of anticancer drug development. Mutation of the Ras protooncogene occurs in 20% of human cancers and results in loss of the response of oncogenic Ras. | Chapter 080. Cancer Cell Biology and Angiogenesis Part 7 Signaling Pathways Downstream of Rtks Ras and PI3K Several oncogene and tumor-suppressor gene products are components of signal transduction pathways that emanate from RTK activation Fig. 80-2 . The most extensively studied are the Ras mitogen-activated protein MAP kinase pathway and the phosphatidylinositol-3-kinase PI3K pathway both of which regulate multiple processes in cancer cells including cell cycle progression resistance to apoptotic signals angiogenesis and cell motility. The development of inhibitors of these pathways is an important avenue of anticancer drug development. Mutation of the Ras protooncogene occurs in 20 of human cancers and results in loss of the response of oncogenic Ras to GTPase-activating proteins GAPs . The constitutively activated GTP-bound Ras activates downstream effectors including the MAP kinase and PI3K Akt pathways. Cancers of the pancreas colon and lung and AML harbor frequent Ras mutations with the KRas allele affected more commonly 85 than N-Ras 15 H-Ras mutations are uncommon in human cancers. In addition Ras activity in tumor cells can be increased by other mechanisms including upregulation of RTK activity and mutation of GAP proteins . NF1 mutations in type I neurofibromatosis . Ras proteins localize to the inner plasma membrane and require posttranslational modifications including addition of a farnesyl lipid moiety to the cysteine residue of the carboxy-terminal CAAX-box motif. Inhibition of RAS farnesylation by rationally designed farnesyltransferase inhibitors FTIs demonstrated encouraging efficacy in preclinical models most of which utilized oncogenic forms of H-Ras. Despite this clinical trials of FTIs in patients whose tumors harbor Ras mutations have been disappointing although some activity has been seen in AML. Upon further study it appears that in the presence of FTIs lipid modification of the K-and N-Ras proteins occurs by addition of a distinct lipid
