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Molecular Mechanisms of Resistance to Imatinib or Sunitinib in KIT Mutants from Patients with Gastrointestinal Stromal Tumors
Author(s) -
Wu Joe C
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.307.2
Subject(s) - sunitinib , imatinib , autophosphorylation , tyrosine kinase , receptor tyrosine kinase , cancer research , gist , imatinib mesylate , tyrosine kinase inhibitor , kinase , mechanism (biology) , stromal cell , biology , cancer , pharmacology , medicine , signal transduction , protein kinase a , microbiology and biotechnology , myeloid leukemia , philosophy , epistemology
The activation of receptor tyrosine kinases (RTKs) is tightly regulated through a variety of mechanisms including autophosphorylation. Dysfunction of the regulatory mechanism frequently results in human diseases such as cancer. A large percentage of gastrointestinal stromal tumors (GISTs) are linked to aberrant activation of the receptor tyrosine kinase KIT, mainly driven by mutations in the juxtamembrane region of the protein. Tyrosine kinase inhibitors sunitinib and imatinib have been used for treatment of GISTs. While the drugs have demonstrated effective clinical benefit for GIST patients via inhibition of KIT, mutations emerge in the activation loop of KIT that render the protein insensitive to the drugs. Biochemical and structural studies that provide insight towards the mechanism of drug action, resistance and selectivity will be presented. In addition, the mechanism by which mutations result in kinase activation and the preferential binding mode of inhibitors to inactive vs. active forms of kinases will be discussed.