Inhibitors of Upstream Inducers of STAT Activation
Activation of STATs, especially STAT3 and STAT5, is commonly observed in solid tumors and hematological malignancies. In several instances the key upstream signaling molecules responsible for STAT activation have been identified. Many of these proteins ar
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Inhibitors of Upstream Inducers of STAT Activation Janani Kumar
Abstract Activation of STATs, especially STAT3 and STAT5, is commonly observed in solid tumors and hematological malignancies. In several instances the key upstream signaling molecules responsible for STAT activation have been identified. Many of these proteins are able to be targeted with specific antibodies or small molecules and so represent attractive candidates for therapeutic development. This chapter details several promising agents that target receptors — both receptor tyrosine kinases and cytokine receptors — and downstream kinases that activate STATs in cancer, including EGFR, VEGFR, IL-6R, SRC and ABL. Keywords EGFR • VEGFR • IL-6R • SRC • ABL • STAT3 • RTK • Inhibitor • Cancer
7.1
Introduction
A number of molecules that mediate STAT activation have been identified in a range of malignancies, several of which are involved in the hyperactivation of STATs observed. These include receptor tyrosine kinases (RTKs), non-receptor tyrosine kinases (non-RTKs) and cytokine receptors, which represent attractive targets for treatment. This has led to the development of a variety of specific inhibitors of these molecules, several of which have shown clinical efficacy. This chapter describes the most important of these inhibitors (Fig. 7.1).
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Epidermal Growth Factor Receptor Inhibitors
Epidermal growth factor receptor (EGFR) and related receptors are known to be active in multiple cancers — where downstream STAT3 activation plays a key role — and have been shown to be validated therapeutic target in several solid tumors [1].
J. Kumar (*) School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia e-mail: [email protected] © Springer International Publishing Switzerland 2016 A.C. Ward (ed.), STAT Inhibitors in Cancer, Cancer Drug Discovery and Development, DOI 10.1007/978-3-319-42949-6_7
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Fig. 7.1 Targeting molecules upstream of STAT activation. Schematic representation of STAT activation by representative RTKs (red), cytokine receptors (green), and non-RTKs (brown), and the downstream phenotypes affected. Inhibitors that target each are indicated (antibodies: purple; small chemicals: blue), with those with multiple targets in italics
7.2.1
Cetuximab
Cetuximab is a humanized mouse monoclonal antibody against epidermal growth factor receptor (EGFR) that acts by interacting with the EGFR ligand-binding domain thereby blocking EGF binding [2], the efficacy of which directly correlated with STAT3 inhibition [3]. The effectiveness of cetuximab was initially demonstrated in colon cancer cells, including suppressed tumor growth in a mouse xenograft model of the disease [4], and has been approved for use in colon cancer with wildtype K-RAS [5]. Cetuximab has also been shown to be effective in inhibiting EGFR-mediated signalling in a variety of other cancers, including head and neck
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squamous epithelial cell cancer, pancreatic cance
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