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  • Review Article
  • Published:

Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

A Corrigendum to this article was published on 04 October 2013

This article has been updated

Key Points

  • Anaplastic lymphoma kinase (ALK) is involved in the initiation and progression of many different cancer types, including lymphomas, neuroblastoma and non-small-cell lung cancer. It is clear that ALK can be activated by translocation, as well as by mutation. The ALK locus is a hotspot for activating translocation events, with 22 different translocation partners identified. The resulting ALK fusion proteins are found in a wide range of cancer types. An alternative mechanism for ALK activation is through point mutation of the ALK locus, most commonly within the kinase domain, as reported in patients with neuroblastoma and thyroid cancer.

  • The physiological function of ALK in mammals is enigmatic, although it is clear that ALK is not required for viability, as Alk−/− mice are viable. The role of ALK in model systems, such as Drosophila melanogaster, Caenorhabditis elegans and Danio rerio, is more clearly defined in development, with ALK signalling used repeatedly in a spatially and temporally regulated manner. In both D. melanogaster and C. elegans, ALK also has genetically defined ligands.

  • The spatial and temporal expression pattern of the different oncogenic ALK fusion proteins is determined by the fusion partners. Furthermore, although not well studied, comparisons of the different ALK fusion proteins suggest that they display differences in signalling and in transforming and tumorigenic potential.

  • The first clinically approved drug to target ALK — crizotinib — is a tyrosine kinase inhibitor (TKI) that was approved by the US Food and Drug Administration (FDA) for use in ALK-positive non-small-cell lung cancer. Recent reports suggest that ALK TKIs will be useful in the treatment of other less frequently occurring ALK-positive cancer types. A number of second-generation ALK TKIs are currently in clinical trials and are able to inhibit secondary 'resistance' mutations that are found in patients treated with crizotinib.

  • Several important issues remain to be addressed, such as cooperativity between ALK and other oncogenes and tumour suppressors, the differences in signalling output between different ALK oncogenes, the streamlined identification of ALK-positive patients in multiple cancer types, putative combinatorial drug strategies for patients and an explanation for why the ALK locus is a hotspot for translocation.

Abstract

The burgeoning field of anaplastic lymphoma kinase (ALK) in cancer encompasses many cancer types, from very rare cancers to the more prevalent non-small-cell lung cancer (NSCLC). The common activation of ALK has led to the use of the ALK tyrosine kinase inhibitor (TKI) crizotinib in a range of patient populations and to the rapid development of second-generation drugs targeting ALK. In this Review, we discuss our current understanding of ALK function in human cancer and the implications for tumour treatment.

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Figure 1: ALK in cancer — an overview.
Figure 2: Signalling downstream of ALK.
Figure 3: Understanding activating ALK mutations at the molecular level.

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Change history

  • 04 October 2013

    In the legend to Figure 3b, the labels for kinase-dead mutations and crizotinib-associated mutations were incorrect and should have read brown and yellow, respectively. This has now been corrected online.

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Acknowledgements

Work in the authors' laboratories has been supported by grants from the Swedish Cancer Society (grant 12–0722 to B.H. and grant 12–0796 to R.H.P.), the Children's Cancer Foundation (grant 11/020 to B.H. and grant 10/065 to R.H.P.), the Swedish Research Council (621-2011-5181 to R.H.P. and grant 521-2012-2831 to B.H.), Lions Cancer Society, Umeå (grant LP 12–1946 to B.H. and R.H.P.) and the JC Kempe Foundation.

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Correspondence to Bengt Hallberg or Ruth H. Palmer.

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Competing interests

B.H. and R.H.P. have previousely recieved crizotinib and funding from Pfizer, as well as LDK378 from Novartis for research purposes.

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Glossary

Dauer

In Caenorhabditis elegans, dauer refers to the entry of the animal into an arrested state when environmental conditions are not favourable for further growth. During the dauer state, feeding is indefinitely arrested and locomotion is markedly reduced. The dauer state ends when the animal experiences favourable conditions.

Neural crest

The neural crest originates from the neural tube and migrates outwards as a transient, multipotent migratory cell population that is unique to vertebrates. The neural crest gives rise to diverse cell lineages, including melanocytes, neuroendocrine cells, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons, and glia.

Iridophore

A pigment cell derived from the neural crest and found in many animals. Iridophores contain crystals that reflect different wavelengths of light, which give them an apparent colour, although no true pigment is present.

Rough-eye phenotype

The disruption of the highly organized pattern of the approximately 800 hexagonal ommatidia in the adult Drosophila melanogaster eye. A rough-eye phenotype can result from the ectopic expression of activated signalling molecules such as anaplastic lymphoma kinase.

Interrenal gland

A structure in close proximity to or embedded in the kidney of fish. Interrenal glands are homologous to the cortical tissue of the mammalian adrenal gland.

Gatekeeper mutations

Mutations of crucial amino acid side chains in many kinases that determine the relative accessibility of the hydrophobic inhibitor-binding pocket, which is located adjacent to the ATP-binding site. The gatekeeper residue does not usually interact with ATP, thus its mutation does not affect the catalytic activity of the enzyme but most commonly interferes with the ability of the small-molecule inhibitor to bind effectively to the enzyme, thus conferring inhibitor resistance.

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Hallberg, B., Palmer, R. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer 13, 685–700 (2013). https://doi.org/10.1038/nrc3580

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