Chapter 080. Cancer Cell Biology and Angiogenesis (Part 7) docx

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 transducti

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

K-Ras allele affected more commonly (85%) than N-K-Ras (15%); H-K-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 (e.g., 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 (geranylgeranyl) through the action of geranylgeranyl transferase-I (GGT-I), which results in restoration of Ras function Thus, while FTIs are likely to have antitumor activity in select human cancers, their mechanism of action appears to occur by inhibition of farnesylation of proteins other than Ras, perhaps RhoB or Rheb (an activator of mTOR) Oncologists anxiously await the development of bona fide Ras-targeted therapeutics

Effector pathways downstream of Ras are also targets of anticancer drug efforts Activation of the Raf serine/threonine kinase is induced by binding to Ras and leads to activation of the MAP kinase pathway (Fig 80-2) Two-thirds of

melanomas and 10% of colon cancers harbor activating mutations in the BRAF

oncogene, leading to constitutive activation of the downstream MAP/ERK kinase (MEK) and extracellular signal-regulated kinases (ERK1/2) This results in the phosphorylation of ERK's cytoplasmic and nuclear targets and alters the pattern of normal cellular gene expression Inhibitors of Raf kinases (e.g., sorafinib) have

entered clinical trials; their activity against tumors expressing mutant BRAF have

been disappointing as single agents, but they appear to increase the activity of chemotherapy in some cases Sorafinib also has significant activity against VEGFRs, and this may account for its clinical activity observed in highly vascular

renal cell cancers (see below) Cells harboring mutant BRAF are highly sensitive

to MEK inhibition, providing another example of "oncogene addiction" (Fig 80-3)

Figure 80-3

Oncogene addiction and synthetic lethality: keys to discovery of new

anti-cancer drugs Panel A Normal cells receive environmental signals that

activate signaling pathways (pathways A, B, and C) that together promote G1 to S phase transition and passage through the cell cycle Inhibition of one pathway (such as pathway A by a targeted inhibitor) has no significant effect due to redundancy provided by pathways B and C In cancer cells, oncogenic mutations lead over time to dependency on the activated pathway, with loss of significant input from pathways B and C The dependency or addiction of the cancer cell to pathway A makes it highly vulnerable to inhibitors that target components of this pathway Clinically relevant examples include Bcr-Abl (CML), amplified

HER2/neu (breast cancer), overexpressed or mutated EGF receptors (lung cancer),

and mutated BRAF (melanoma) Panel B Genes are said to have a synthetic lethal

relationship when mutation of either gene alone is tolerated by the cell, but

mutation of both genes leads to lethality Thus, in the example, mutant gene a and

gene b have a synthetic lethal relationship, implying that the loss of one gene

makes the cell dependent on the function of the other gene In cancer cells, loss of

function of a tumor-suppressor gene (wild-type designated gene A; mutant designated gene a) may render the cancer cells dependent on an alternative pathway of which gene B is a component As shown in the figure, if an inhibitor

of gene B can be identified, this can cause death of the cancer cell, without harming normal cells (which maintain wild-type function for gene A)

High-throughput screens can now be performed using isogenic cell line pairs in which one cell line has a defined defect in a tumor-suppressor pathway Compounds can

be identified that selectively kill the mutant cell line; targets of these compounds have a synthetic lethal relationship to the tumor-suppressor pathway, and are potentially important targets for future therapeutics Note that this approach allows discovery of drugs that indirectly target deleted tumor-suppressor genes and hence greatly expands the list of physiologically relevant cancer targets