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The anaplastic lymphoma kinase in the pathogenesis of cancer

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.

Abstract

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.

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Figure 1: ALK and Ras–ERK.
Figure 2: ALK and STATs.
Figure 3: ALK and PI3K.
Figure 4: ALK and CD30 signalling.

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Acknowledgements

This work was supported by National Institutes of Health grant number R01-CA64033, Sixth Research Framework Program of the European Union, Project RIGHT (LSHB-CT-2004-005276), Ministero dell'Università e Ricerca Scientifica (MUR), Ministero della Salute, Associazione Italiana per la Ricerca sul Cancro, Regione Piemonte, Compagnia di San Paolo Torino (Progetto Oncologia), Fondazione Cassa di Risparmio di Torino and Fondazione Guido Berlucchi per la Ricerca sul Cancro. Roberto Piva was supported by the MUR programme 'Incentivazione alla mobilità di studiosi residenti all'estero'. Claudia Voena was supported by a fellowship from the Fondazione Italiana per la Ricerca sul Cancro.

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Correspondence to Roberto Chiarle or Giorgio Inghirami.

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Supplementary information

Supplementary information S1 (movie)

Morphology and dynamics of untreated anaplastic large cell lymphoma (ALCL) cells. Untreated human ALCL cells were photographed with confocal microscopy every 5 min. ALCL cells spontaneously display an activated-like T-cell morphology, with actin-rich membrane protrusions. The high dynamics of the membrane protrusions is a typical feature of ALCL cells. (MOV 7736 kb)

Supplementary information S2 (movie)

Changes in morphology and dynamics of anaplastic large cell lymphoma (ALCL) cells after anaplastic lymphoma kinase (ALK) inhibition. Human ALCL cells were treated with the specific ALK inhibitor and photographed with confocal microscopy every 5 min. On treatment with ALK inhibitor, ALCL cells first revert to a round, symmetrical shape and lose their membrane protrusions. Subsequently, after a prolonged treatment, ALCL cells undergo apoptosis. (MOV 4693 kb)

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DATABASES

Atlas of Genetics and Cytogenetics in Oncology and Haematology

ALK

FURTHER INFORMATION

Allen Brain Atlas

ClinicalTrials.gov

European Association for Haematopathology

RNA Interference Technology as Human Therapeutic Tool

Glossary

Anaplasia

Loss of structural differentiation within a cell or group of cells, often with increased capacity for multiplication, as in a malignant tumour.

Histiocyte

A general term for cells of monocytic lineage. When histiocytes show evident phagocytic activity they are called macrophages. For tumours, the term histiocytic refers either to a proven or supposed derivation of the neoplastic cells from normal hystiocytes or to tumours in which neoplastic cells are mixed with abundant reactive histiocytes.

Pseudonuclear inclusions

A peculiar aspect of cells in which the nucleus appears to enclose a region of cytoplasm within a ring; such cells are called doughnut cells.

Immunoblastic or plasmablastic morphology

Morphology that resembles plasmablasts. Plasmablasts are cells that have the blastoid morphology of immunoblasts but have acquired the antigen profile of a plasma cell. They are large cells with abundant basophilic cytoplasm and round to oval nuclei with single or several prominent nucleoli.

Dependence receptor

A transmembrane protein that is capable of inducing cell death in the absence of the required stimulus but which blocks apoptosis following binding to their ligand. Expression of these receptors creates cellular states of dependence on the associated ligands.

WD domain

WD repeats are short amino-acid motifs terminating in Trp–Asp (W–D). WD domain-containing proteins have 4 to 16 repeating units and are implicated in signal transduction, transcription regulation, cell-cycle control and apoptosis.

Guanine nucleotide exchange factor

(GEF). A regulatory molecule that catalyses the exchange of GDP for GTP on GTPases in response to diverse extracellular stimuli, and ultimately regulates numerous cellular responses such as proliferation, differentiation and movement.

GTPase-activating protein

(GAP). A regulatory molecule that enhances the intrinsic GTPase activity of GTPase proteins.

Reed–Sternberg cell

Diagnostic giant cell of B lineage found in Hodgkin lymphoma. It is characterized by multiple or multilobulated nuclei and prominent eosinophilic nucleoli.

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Chiarle, R., Voena, C., Ambrogio, C. et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 8, 11–23 (2008). https://doi.org/10.1038/nrc2291

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