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...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 7) 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 ofsignal transduction pathways that emanate from RTK activation (Fig. 80-2). Themost extensively studied are the Ras/mitogen-activated protein (MAP) kinasepathway and the phosphatidylinositol-3-kinase (PI3K) pathway, both of whichregulate multiple processes in cancer cells, including cell cycle progression,resistance to apoptotic signals, angiogenesis, and cell motility. The developmentof inhibitors of these pathways is an important avenue of anticancer drugdevelopment. Mutation of the Ras protooncogene occurs in 20% of human cancers andresults in loss of the response of oncogenic Ras to GTPase-activating proteins(GAPs). The constitutively activated, GTP-bound Ras activates downstreameffectors including the MAP kinase and PI3K/Akt pathways. Cancers of thepancreas, colon, and lung and AML harbor frequent Ras mutations, with the K-Ras allele affected more commonly (85%) than N-Ras (15%); H-Ras mutationsare uncommon in human cancers. In addition, Ras activity in tumor cells can beincreased by other mechanisms, including upregulation of RTK activity andmutation of GAP proteins (e.g., NF1 mutations in type I neurofibromatosis). Rasproteins localize to the inner plasma membrane and require posttranslationalmodifications, including addition of a farnesyl lipid moiety to the cysteine residueof the carboxy-terminal CAAX-box motif. Inhibition of RAS farnesylation byrationally designed farnesyltransferase inhibitors (FTIs) demonstrated encouragingefficacy in preclinical models, most of which utilized oncogenic forms of H-Ras.Despite this, clinical trials of FTIs in patients whose tumors harbor Ras mutationshave been disappointing, although some activity has been seen in AML. Uponfurther 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 (geranylgeranyl) throughthe action of geranylgeranyl transferase-I (GGT-I), which results in restoration ofRas function. Thus, while FTIs are likely to have antitumor activity in selecthuman cancers, their mechanism of action appears to occur by inhibition offarnesylation of proteins other than Ras, perhaps RhoB or Rheb (an activator ofmTOR). Oncologists anxiously await the development of bona fide Ras-targetedtherapeutics. Effector pathways downstream of Ras are also targets of anticancer drugefforts. Activation of the Raf serine/threonine kinase is induced by binding to Rasand leads to activation of the MAP kinase pathway (Fig. 80-2). Two-thirds ofmelanomas and 10% of colon cancers harbor activating mutations in the BRAFoncogene, leading to constitutive activation of the downstream MAP/ERK kinase(MEK) and extracellular signal-regulated kinases (ERK1/2). This results in thephosphorylation of ERKs cytoplasmic and nuclear targets and alters the pattern ofnormal cellular gene expression. Inhibitors of Raf kinases (e.g., sorafinib) haveentered clinical trials; their activity against tumors expressing mutant BRAF havebeen disappointing as single agents, but they appear to increase the activity ofchemotherapy in some cases. Sorafinib also has significant activity againstVEGFRs, and this may account for its clinical activity observed in highly vascularrenal cell cancers (see below). Cells harboring mutant BRAF are highly sensitiveto MEK inhibition, providing another example of oncogene addiction (Fig. 80-3). Figure 80-3 Oncogene addiction and synthetic lethality: keys to discovery of newanti-cancer drugs. Panel A. Normal cells receive environmental signals thatactivate signaling pathways (pathways A, B, and C) that together promote G1 to Sphase transition and passage through the cell cycle. Inhibition of one pathway(such as pathway A by a targeted inhibitor) has no significant effect due toredundancy provided by pathways B and C. In cancer cells, oncogenic mutationslead over time to dependency on the activated pathway, with loss of significantinput from pathways B and C. The dependency or addiction of the cancer cell topathway A makes it highly vulnerable to inhibitors that target components of thispathway. Clinically relevant examples include Bcr-Abl (CML), amplifiedHER2/neu (breast cancer), overexpressed or mutated EGF receptors (lung cancer),and mutated BRAF (melanoma). Panel B. Genes are said to have a synthetic lethalrelationship when mutation of either gene alone is tolerated by the cell, butmutation of both genes leads to lethality. Thus, in the example, mutant gene a andgene b have a synthetic lethal rel ...