Page 1232 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPTER 88 Protein Kinase Antagonists 1195

the TCR or the IL-2 receptor is able to trigger ERK signaling in has been frustrated by either unacceptable toxicity or poor efficacy.
25
T cells. Two small-molecule inhibitors of this serine/threonine Currently, a new generation of p38 MAPK inhibitors are being
kinase pathway are undergoing clinical trials: the farnesyl inhibitor assessed in phase II trials for the treatment of chronic obstructive
of Ras tipifarnib, which is in phase III trials for the treatment pulmonary disease (COPD); losmapimod has recently failed
of acute myeloid leukemia; and the multikinase inhibitor phase II testing because of lack of efficacy, and AZD7624
sorafenib, which is FDA approved for the treatment of renal cell (AstraZeneca, Cambridge, UK) and acumapimod are still being
26
carcinoma. Sorafenib is relatively well tolerated despite its ability investigated.
to inhibit numerous kinases, including the M3K RAF, as well as
receptor tyrosine kinases, including platelet-derived growth factor CONCLUSIONS
receptor (PDGFR), VEGFR, Kit, and FLT-3. Its role as an immu-
nosuppressant has yet to be explored. There are three RAF
isoforms: A-RAF, B-RAF, and C-RAF. A number of cancers are ON THE HORIZON
associated with B-RAF mutations resulting in a constitutively • Many kinase inhibitors, initially designed as antitumor agents, have
active kinase, the best known of which is the V600E mutation. been repurposed as immunosuppressants (e.g., ruxolitinib).
Two kinase inhibitors, vemurafenib and dabrafenib, which are • Further understanding of the pathophysiology of autoimmune disease
highly active against the B-RAF V600E kinase, are FDA licensed will lead to the increased use and creation of kinase inhibitors.
for the treatment of melanoma. Their early use was associated • Increasing use of specific kinase inhibitors may improve our understand-
with a partial and short-lived inhibition of the MAPK pathway ing of the pathophysiology of autoimmune disease.
as C-RAF signaling was preserved, which is often hyperactivated
by upstream mutations in Ras signaling or by the presence of Scientific advances in the 1990s have led to the discovery of
B-RAF V600E, which is able to dimerize and activate C-RAF many novel intracellular signaling pathways that link membrane-
27
even in the presence of inhibitors. Moreover, clinical trials are bound receptor and cytokine signaling with alteration of gene
ongoing for the treatment of the histiocytosis known as Erdheim- expression and cellular activation necessary to trigger an immune
Chester disease, for which B-RAF mutations have shown to be cell response. Many of these pathways are interlinked to make
present in the vast majority of the case. up a complex array of networks composed of enzymes, adaptor
The M2K MEK1 and the MAPK ERK1 lie downstream of proteins, and transcription factors, all of which are potential
RAF. Cobimetinib and trametinib are selective MEK inhibitors targets for drug discovery in the quest to make a therapy that
that are FDA licensed for the treatment of melanoma both as a will be able to treat a specific autoimmune disease without an
single agent and in combination with B-RAF V600E inhibitors unacceptable degree of immunosuppression. Now more than a
28
as they are able to block residual C-RAF signaling. Although decade since the identification of many new targets, the first
all of these agents are seen as anticancer drugs rather than generation of drugs designed to interfere with specific immune
immunosuppressants, it is of note that cobimetinib is currently cell signals are being brought to the clinic. The success of the
being assessed in the treatment of Langerhans cell histiocytosis anticancer BCR-Abl inhibitor imatinib and the immunosup-
(LCH). LCH is a clonal disorder characterized both by the B-RAF pressive mTOR inhibitor sirolimus has placed the protein kinases
V600E mutation in histiocytes and by the presence of inflam- center stage as targets of future drug discovery. As many of the
matory lesions that often respond to simple corticosteroid therapy. key steps in the activation of an immune cell are often shared
Selective inhibitors of ERK have been developed: FR180204 has with those that allow a cancer cell to proliferate, many of these
been shown to inhibit the development of collagen-induced agents are being tested as anticancer drugs rather than as
arthritis in mice and is being considered as an agent in the immunosuppressants. Despite this, some agents, such as the
treatment of RA. CC90003 (Celgene, Summit, NJ) is currently mTOR inhibitors, originally intended for the treatment of cancer
being assessed in a phase I trial in patients with solid tumors. have been far more successful in the field of immunology, and
this may continue to be true for future modifiers of cell signaling.
The JNK Cascade Conversely, JAK inhibitors could potentially be used in the
Another limb of the MAPK pathway is the JNK pathway. Many treatment of lymphoma. Either way, we are likely to see a large
inflammatory agents, including lipopolysaccharide (LPS), TNF-α, number of novel immunosuppressants appear both serendipi-
25
and IL-1 are able to activate the JNK pathway. In synoviocytes, tously and intentionally as new protein kinase inhibitors are
this results in secretion of proteases implicated in joint destruction licensed for a wide range of debilitating illnesses.
29
seen in RA. A number of small-molecule inhibitors of JNKs
have been identified and are currently being investigated in the Please check your eBook at https://expertconsult.inkling.com/
treatment of inflammation, cancer, and neurological diseases. for self-assessment questions. See inside cover for registration
XG102 (Xigen Ltd., Bedford, UK) is being assessed in phase III details.
trials for the treatment of ocular inflammation and sensorineural
hearing loss.
REFERENCES
The p38 MAPK Cascade
This cascade was originally identified as part of a drug screen 1. Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved
looking for inhibitors of TNF-α–mediated inflammatory features and deduced phylogeny of the catalytic domains. Science
1988;241:42–52.
30
responses. TLR-dependent production of IL-1 and TNF-α is 2. Noble ME, Endicott JA, Johnson LN. Protein kinase inhibitors: insights
p38 MAPK dependent. The success of TNF-α–blocking antibodies into drug design from structure. Science 2004;303:1800–5.
in the treatment of RA has led to much interest in the development 3. Druker BJ, Lydon NB. Lessons learned from the development of an Abl
of p38 MAPK inhibitors. However, although many p38 inhibitors tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest
have been reported, their development into therapeutic drugs 2000;105:3–7.