Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy

Abstract

Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, was initially identified in constitutively activated oncogenic fusion forms – the most common being nucleophosmin-ALK – in anaplastic large-cell lymphomas, and subsequent studies have identified ALK fusions in diffuse large B-cell lymphomas, systemic histiocytosis, inflammatory myofibroblastic tumors, esophageal squamous cell carcinomas and non-small-cell lung carcinomas. More recently, genomic DNA amplification and protein overexpression, as well as activating point mutations, of ALK have been described in neuroblastomas. In addition to those cancers for which a causative role for aberrant ALK activity is well validated, more circumstantial links implicate the full-length, normal ALK receptor in the genesis of other malignancies – including glioblastoma and breast cancer – via a mechanism of receptor activation involving autocrine and/or paracrine growth loops with the reported ALK ligands, pleiotrophin and midkine. This review summarizes normal ALK biology, the confirmed and putative roles of ALK in the development of human cancers and efforts to target ALK using small-molecule kinase inhibitors.

Keywords::

• anaplastic large-cell lymphoma
• anaplastic lymphoma kinase
• esophageal squamous cell carcinoma
• glioblastoma
• inflammatory myofibroblastic tumor
• midkine
• neuroblastoma
• non-small-cell lung carcinoma
• pleiotrophin
• targeted cancer therapy
• tyrosine kinase inhibitor

Financial & competing interests disclosure

Thomas R Webb is a coinventor on patents that describe the synthesis and characterization of anaplastic lymphoma kinase (ALK) small-molecule inhibitors designed by ChemBridge Research Laboratories. A Thomas Look and Stephan W Morris are coinventors on patents concerned with the discovery of ALK, the use of methods to detect ALK for diagnostic purposes, and the targeting of ALK for therapeutic indications. Studies cited in this review performed in the authors’ laboratories were supported in part by NIH grants R01 CA69129 (Stephan Morris) and Cancer Center CORE grant CA21765, and by the American Lebanese Syrian Associated Charities, St Jude Children’s Research Hospital. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.