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The anaplastic lymphoma kinase in the pathogenesis of cancer
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Journal Article
The anaplastic lymphoma kinase in the pathogenesis of cancer
2008
Overview
Key Points
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase first identified in a chromosomal translocation associated with some anaplastic large cell lymphomas (ALCL), a subset of T-cell non-Hodgkin lymphomas.
The function of the full-length ALK receptor is still poorly characterized. Recent data suggest that ALK is involved in neuronal cell differentiation and regeneration, synapse formation and muscle cell migration.
Recently, the interest on ALK in oncology has increased considerably, following the discovery of ALK translocations in a fraction of non-small-cell lung cancers and in other solid tumours.
In cancers, all translocations involving ALK produce fusion proteins with constitutive tyrosine kinase activity that in most cases derives from spontaneous dimerization induced by the different fusion partners.
Constitutive ALK activity in cancers results in the activation of several downstream pathways that are shared with other tyrosine kinases. Many of these pathways have already been characterized.
Constitutive ALK signalling induces cell transformation
in vitro
and
in vivo
by controlling key cellular processes such as cell-cycle progression, survival, cell migration and cell shaping.
ALK represents an attractive target for innovative combination therapies based on selective small-molecule inhibitors of its tyrosine kinase activity or on its use as an oncoantigen for tumour vaccination.
The receptor tyrosine kinase anaplastic lymphoma kinase (ALK) was first identified as part of a chromosomal translocation associated with some anaplastic large cell lymphomas (ALCLs). Now data are emerging that indicate that ALK might be a valid therapeutic target in ALCL and that it could also be involved in other cancers.
Tyrosine kinases are involved in the pathogenesis of most cancers. However, few tyrosine kinases have been shown to have a well-defined pathogenetic role in lymphomas. The anaplastic lymphoma kinase (ALK) is the oncogene of most anaplastic large cell lymphomas (ALCL), driving transformation through many molecular mechanisms. In this Review, we will analyse how translocations or deregulated expression of ALK contribute to oncogenesis and how recent genetic or pharmacological tools, aimed at neutralizing its activity, can represent the basis for the design of powerful combination therapies.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Humans
/ Lymphoma, Large B-Cell, Diffuse - enzymology
/ Lymphoma, Large B-Cell, Diffuse - genetics
/ Lymphoma, T-Cell - enzymology
/ Protein-Tyrosine Kinases - antagonists & inhibitors
/ Protein-Tyrosine Kinases - genetics
/ Protein-Tyrosine Kinases - metabolism
/ Receptor Protein-Tyrosine Kinases - metabolism
/ T cells
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