Page 1231 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1194 PART TEN Prevention and Therapy of Immunological Diseases

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IKK kinases (IKKKs), of which PKC and PKB are members, of p70 S6K1 and inactivation of 4E-BP1, which are critical for
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regulate IκB. Several IKK inhibitors have been in development; translation of new proteins.
however, all of them have failed clinical trials. As its name suggests, mTOR is inhibited by the macrolide
rapamycin, now licensed as the drug sirolimus for the treatment
Lipid Kinases and Downstream Signaling of graft rejection. Sirolimus does not inhibit mTOR by directly
Kinases are also important in phosphorylating lipids, and these binding to the ATP-binding pocket but acts indirectly, associating
modifications are very relevant in signal transduction through with FK506-binding protein 12 (FKBP12). This, in turn, inhibits
both the TCR and cytokine receptors. In addition to the produc- the kinase complex made up of mTOR, mLST8, and raptor
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tion of inositol triphosphate by the action of PLCγ1, there is a (mTORC1). It was hoped that sirolimus would be a potent
second pathway of inositol lipid metabolism regulated by the anticancer drug, but it has met limited success in this regard. In
TCR that is a response shared by costimulatory molecules, such contrast, it has been successfully used as an immunosuppressant,
as CD28, cytokines, and chemokines. This response is mediated typically as part of a combination regimen for allograft rejection
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by the class I group of phosphatidyl-inositol 3 kinases (PI3Ks), prophylaxis. In view of the ubiquitous expression of mTOR
which is composed of four isoforms (PI3Kα to -δ), which and its role in protein translation, it is not surprising that sirolimus
phosphorylate the 3’-OH position of the inositol ring of would be associated with a number of side effects, including
phosphatidyl-inositol (4,5) bisphosphate (PI(4,5)P 2 ) to produce hyperlipidemia, hypertriglyceridemia, myelosuppression, and
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PI(3,4,5)P 3 . This lipid and its metabolite PI(3,4)P 2 bind to the delayed wound healing. There is some evidence of renal toxicity,
pleckstrin homology (PH) domains of proteins and either induce but this is minor compared with that caused by the calcineurin
localization of the protein to defined areas of the plasma mem- inhibitors cyclosporine and tacrolimus. Myelosuppression associ-
brane, where activation can occur, or induce conformational ated with sirolimus is typically dose related and rapidly reversible,
changes that allow for allosteric modifications of activity. Targets even in patients receiving the drug for chronic GvHD.
for D-3 phosphoinositides in T cells include a number of There are currently three rapamycin derivatives, namely,
downstream protein serine/threonine kinases and the Rac-1 and temsirolimus, everolimus, and AP23573, undergoing clinical
RhoA guanine nucleotide exchange proteins. Small-molecule trials. Everolimus is licensed for use in the management of heart,
inhibitors of PI3’K, Wortmannin and LY294002, are both potent liver, and kidney transplantation in conjunction with cyclosporine.
inhibitors of T-cell activation, although toxicity prevents either It is under investigation for the treatment of arthritis and a
from being clinically useful. In contrast to the more widely number of solid tumors. Temsirolimus is licensed for the treatment
expressed PI3’Kα and β, PI3’Kγ and -δ are only expressed in of renal cell carcinoma and mantle cell lymphoma. The introduc-
hematopoietic tissue and deletion of PI3’Kγ results in defective tion of novel rapamycin derivatives has been joined by the
migration of neutrophils and macrophages to sites of inflam- introduction of pan-mTOR direct inhibitors AZD2014 (Astra-
mation without other pathology. This limited expression makes Zeneca, Cambridge, UK) and CC-223 (Celgene, Summit, NJ),
PI3’Kγ a potentially useful target, and selective PI3’Kγ inhibitors both of which are in phase II trials for the treatment of non-
have shown to be effective in mouse models of collagen-induced Hodgkin lymphoma and solid tumors.
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arthritis. For similar reasons, PI3’Kδ is another attractive target
for which the inhibitor idelalisib was FDA-approved for the MAPK Pathways
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treatment of lymphoma. Over 25 other inhibitors of PI3’K are The MAPK family constitute a complex phospho-relay system
currently being studied in preclinical and clinical trials and include of signal transduction, composed of three sequentially activated
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buparlisib, which is in a phase III trial for the treatment of breast kinases that are themselves modulated by phosphorylation.
cancer. Substrates of MAPK pathways include transcription factors,
One PI(3,4,5)P 3 -regulated kinase activated by the TCR is phospholipases, cytoskeletal proteins, and other protein kinases.
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protein kinase B (PKB/AKT). T cells stimulated in the presence Three main MAPK cascades have been identified in mammalian
of the PI3’K inhibitors Wortmannin or LY-294002 fail to activate cells: the extracellular signal regulated kinase (ERK) cascade, the
and proliferate. The ability of cells to take up nutrients and Jun kinase (JNK) cascade, and the p38 MAPK cascade. All start
switch on glycolysis is essential for lymphocyte activation; PKB with a membrane-localized activator followed by three MAPKs
is proposed to be the main effector that mediates the action of that sequentially phosphorylate each other (see Fig. 88.3). The
PI3’K on these fundamentally important metabolic pathways. top level of kinases is termed MAPK kinase kinases (MAPKKKs,
There are three PKB isoforms (PKB-α, -β, -γ, or AKT1, -2, -3, MKKKs, or Map3Ks). The middle level MAPK kinases (MAPKKs,
respectively), and T cells lacking both Akt1 and Akt2 are greatly MKKs, or Map2Ks) phosphorylate a common Thr-Xaa-Tyr motif,
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impaired. Specific inhibitors of PKB are in clinical trials with where Xaa is any amino acid. The lowest tier consists of the
mixed results; MK-2206 (Merck, Kenilworth, NJ), AZD-5363 MAPKs that phosphorylate Ser/Thr-Pro motifs. Each pathway
(Astra Zeneca, Cambridge, UK), and uprosertib are all in terminates in the phosphorylation of substrate proteins.
phase II trials for the treatment of several malignancies (see
Table 88.3). The ERK Cascade
In addition to glucose metabolism, the PI3’K-regulated serine/ ERK1 and 2 were identified as kinases that were activated in
threonine kinase mammalian target of rapamycin (mTOR) response to growth factor stimulation, which are mimicked by
regulates protein synthesis in response to cellular nutrient and expression of constitutively active Ras. The link between active
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energy levels. It is activated not only by a number of growth Ras and subsequent phosphorylation of the ERKs was made
factor receptors but also by cytokines, including IL-2. Many both by the discovery of the MAPK kinase MEK1 and its phos-
signaling pathways link growth factor receptors with activation phorylation by the known Ras effector RAF1, now known as a
of mTOR, including the adenosine monophosphate (AMP)– MAPK kinase kinase (M3K). The ERK cascade is ubiquitous in
dependent kinase (AMPK) and phosphatidyl inositol 3’ kinase mammalian cells and is generally considered one of the main
(PI3’K) (see Fig. 88.4). mTOR promotes cell growth by activation effector pathways regulated by the GTPase p21ras. Activation of