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.

Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome

“…The most homologous kinase receptor to LTK is ALK. ALK is a target for cancer therapy by a small-molecule kinase inhibitor (21,22). Pleiotrophin and midkine have been proposed as its ligands (23,24).…”

Renal cell carcinoma with novel VCL–ALK fusion: new representative of ALK-associated tumor spectrum

“…24,25 ALK belongs to the insulin receptor superfamily of receptor tyrosine kinases and is ontogenetically silenced in mature human tissues with the exception of certain areas of the brain; however, full-length ALK is expressed in some pediatric sarcomas. 26 A total of 16 ALK fusion oncogenes have been reported; all include an obligatory 3 0 portion encoding for the kinase domain. The various 5 0 partners differ in their function and subcellular localization but are similar in their ubiquitous expression and homopolymerization properties of respective products that lead to an ectopic expression and constitutive activation of the ALK.…”

Anaplastic lymphoma kinase: Role in cancer and therapy perspective

“…However, ALK-targeted therapy is likely to benefit ALK-positive DLBCL patients. 47 So far, 22 different genes have been described as being translocated with ALK ( Fig. 3) and, adding to the complexity, within the different ALK fusion there are examples of several breakpoint variants, as illustrated by the EML4-ALK translocations observed in NSCLC, by which multiple EML4 exon breakpoints fuse in-frame with exon 20 of ALK.…”