Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

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Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

Bengt Hallberg and Ruth H.Palmer

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.

Anaplastic lymphoma kinase (ALK) was discovered through the identification of a 2;5 chromosomal translocation in anaplastic large-cell non-Hodgkins lymphoma (ALCL)1. The nucleophosmin (NPM) ALK fusion protein produced by this rearrangement1,2

results in constitutive activation of the ALK kinase, which is normally regulated by the extracellular ligand-binding domain in the full-length receptor1,3,24. We

now know that ALK activation in cancer can also arise through overexpression and mutation of full-length ALK46 (FIG.1). Just when and where does ALK activation become a troublemaker in the context of human tumours? ALK alterations have been described in several human cancers, but it is not fully understood whether these reflect a true tumorigenic role of ALK. In the case of ALK translocations, the ALK fusion proteins that have been examined seem to have an important role in driving tumorigenesis. In tumours in which full-length ALK is mutated, such as in neuroblastoma and thyroid cancer, the picture is less clear, although the overriding genetic evidence in neuroblastoma implicates mutant ALK as an important oncoprotein.

ALK functionALK function in mice and humans. The single ALK

locus in mice and humans encodes a classical receptor tyrosine kinase (RTK) that comprises an extracellular ligand-binding domain, a transmembrane domain and an intracellular tyrosine kinase domain (FIG.2). Together with the related leukocyte tyrosine kinase (LTK) receptor, ALK constitutes a subfamily within the insulin receptor superfamily on the basis of kinase domain similarities. The extracellular domains of ALK and LTK are unique among RTKs, as they contain a glycine-rich

region and, in the case of ALK, additional LDLa and MAM domains6. Pleiotrophin (PTN) and midkine (MK) have been reported as activating ligands for mammalian ALK7,8. These small heparin-binding...