Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy.
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.
Webb
Thomas R
TR
Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 332 North Lauderdale Street, Mail Stop 1000, Memphis, TN 38105, USA.
Slavish
Jake
J
George
Rani E
RE
Look
A Thomas
AT
Xue
Liquan
L
Jiang
Qin
Q
Cui
Xiaoli
X
Rentrop
Walter B
WB
Morris
Stephan W
SW
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D000078792:Midkine; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C066845:pleiotrophin; D000078792:Midkine; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases