Role of KIT and platelet-derived growth factor receptors as oncoproteins.
KIT and platelet-derived growth factor receptors (PDGFRs) play critical oncogenic roles in a broad spectrum of hematologic and solid tumors. These receptor tyrosine kinases, as well as ABL and BCR-ABL, are inhibited by imatinib. Tumors caused by chromosomal translocations that lead to overexpression of PDGFR ligand, resulting in continuous activation of wild-type PDGFRs, are likely to respond to imatinib, as are malignancies caused by gene amplification and overexpression of wild-type PDGFR or KIT receptors. Malignancies linked to chromosomal translocations that express PDGFR or KIT fusion protein-tyrosine kinases are also likely to respond to imatinib. Malignant cell responses to imatinib depend on whether any of these tyrosine kinase activities play essential roles in the oncogenesis of a given tumor, as well as the precise molecular mechanism underlying oncogenesis. For example, imatinib efficacy for malignancies arising from constitutively activating point mutations in tyrosine kinases depends on the exact location of the mutation in the kinase molecule.
Fletcher
Jonathan A
JA
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D019089:Stem Cell Factor
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha