Development of Anaplastic Lymphoma Kinase (ALK) Small-molecule Inhibitors for Cancer Therapy

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) involved in the genesis of several human cancers; indeed, ALK was initially identified in constitutively activated and oncogenic fusion forms--the most common being nucleophosmin (NPM)-ALK--in a non-Hodgkin's lymphoma (NHL) known as anaplastic large-cell lymphoma (ALCL) and subsequent studies identified ALK fusions in the human sarcomas called inflammatory myofibroblastic tumors (IMTs). In addition, two recent reports have suggested that the ALK fusion, TPM4-ALK, may be involved in the genesis of a subset of esophageal squamous cell carcinomas. While the cause-effect relationship between ALK fusions and malignancies such as ALCL and IMT is very well established, more circumstantial links implicate the involvement of the full-length, normal ALK receptor in the genesis of additional malignancies including glioblastoma, neuroblastoma, breast cancer, and others; in these instances, ALK is believed to foster tumorigenesis following activation by autocrine and/or paracrine growth loops involving the reported ALK ligands, pleiotrophin (PTN) and midkine (MK). There are no currently available ALK small-molecule inhibitors approved for clinical cancer therapy; however, recognition of the variety of malignancies in which ALK may play a causative role has recently begun to prompt developmental efforts in this area. This review provides a succinct summary of normal ALK biology, the confirmed and putative roles of ALK fusions and the full-length ALK receptor in the development of human cancers, and efforts to target ALK using small-molecule kinase inhibitors.