Abstract
Deregulated activation of protein tyrosine kinases (PTKs) is a frequent event underlying malignant transformation in many types of cancer. The formation of oncogenic fusion tyrosine kinases (FTKs) resulting from genomic rearrangements, represents a common mechanism by which kinases escape the strict controls that normally regulate their expression and activation. FTKs are typically composed of an N-terminal dimerisation domain, provided by the fusion partner protein, fused to the kinase domain of receptor or nonreceptor tyrosine kinases (non-RTKs). Since FTKs do not contain extracellular domains, they share many characteristics with non-RTKs in terms of their properties and approaches for therapeutic targeting. FTKs are cytoplasmic or sometimes nuclear proteins, depending on the normal distribution of their fusion partner. FTKs no longer respond to ligand and are instead constitutively activated by dimerisation induced by the fusion partner. Unlike RTKs, FTKs cannot be targeted by therapeutic antibodies, instead they require agents that can cross the cell membrane as with non-RTKs. Here we review the PTKs known to be expressed as FTKs in cancer and the strategies for molecularly targeting these FTKs in anti-cancer therapy.
Keywords: Oncogenic fusion proteins, anti-cancer therapy, tyrosine kinase, small molecule inhibitors
Anti-Cancer Agents in Medicinal Chemistry
Title: Oncogenic Fusion Tyrosine Kinases as Molecular Targets for Anti-Cancer Therapy
Volume: 7 Issue: 6
Author(s): Rosalind H. Gunby, Elisa Sala, Carmen J. Tartari, Miriam Puttini, Carlo Gambacorti-Passerini and Luca Mologni
Affiliation:
Keywords: Oncogenic fusion proteins, anti-cancer therapy, tyrosine kinase, small molecule inhibitors
Abstract: Deregulated activation of protein tyrosine kinases (PTKs) is a frequent event underlying malignant transformation in many types of cancer. The formation of oncogenic fusion tyrosine kinases (FTKs) resulting from genomic rearrangements, represents a common mechanism by which kinases escape the strict controls that normally regulate their expression and activation. FTKs are typically composed of an N-terminal dimerisation domain, provided by the fusion partner protein, fused to the kinase domain of receptor or nonreceptor tyrosine kinases (non-RTKs). Since FTKs do not contain extracellular domains, they share many characteristics with non-RTKs in terms of their properties and approaches for therapeutic targeting. FTKs are cytoplasmic or sometimes nuclear proteins, depending on the normal distribution of their fusion partner. FTKs no longer respond to ligand and are instead constitutively activated by dimerisation induced by the fusion partner. Unlike RTKs, FTKs cannot be targeted by therapeutic antibodies, instead they require agents that can cross the cell membrane as with non-RTKs. Here we review the PTKs known to be expressed as FTKs in cancer and the strategies for molecularly targeting these FTKs in anti-cancer therapy.
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Cite this article as:
Gunby H. Rosalind, Sala Elisa, Tartari J. Carmen, Puttini Miriam, Gambacorti-Passerini Carlo and Mologni Luca, Oncogenic Fusion Tyrosine Kinases as Molecular Targets for Anti-Cancer Therapy, Anti-Cancer Agents in Medicinal Chemistry 2007; 7 (6) . https://dx.doi.org/10.2174/187152007784111340
DOI https://dx.doi.org/10.2174/187152007784111340 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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