Oncogenic fusion tyrosine kinases as molecular targets for anti-cancer therapy.
Deregulated activation of protein tyrosine kinases (PTKs) is a frequent event underlying malignant transformation in many types of cancer. The formation of oncogenic fusion tyrosine kinases (FTKs) resulting from genomic rearrangements, represents a common mechanism by which kinases escape the strict controls that normally regulate their expression and activation. FTKs are typically composed of an N-terminal dimerisation domain, provided by the fusion partner protein, fused to the kinase domain of receptor or non-receptor tyrosine kinases (non-RTKs). Since FTKs do not contain extracellular domains, they share many characteristics with non-RTKs in terms of their properties and approaches for therapeutic targeting. FTKs are cytoplasmic or sometimes nuclear proteins, depending on the normal distribution of their fusion partner. FTKs no longer respond to ligand and are instead constitutively activated by dimerisation induced by the fusion partner. Unlike RTKs, FTKs cannot be targeted by therapeutic antibodies, instead they require agents that can cross the cell membrane as with non-RTKs. Here we review the PTKs known to be expressed as FTKs in cancer and the strategies for molecularly targeting these FTKs in anti-cancer therapy.
Department of Clinical Medicine, University of Milano-Bicocca, Monz, Italy. rosalind.gunby@unimib.it
Rosalind H
RH
Gunby
Elisa
E
Sala
Carmen J
CJ
Tartari
Miriam
M
Puttini
Carlo
C
Gambacorti-Passerini
Luca
L
Mologni
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry* / Q000627:therapeutic use; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D015514:Oncogene Proteins, Fusion; D020794:Receptor Protein-Tyrosine Kinases