c-KIT Inhibitor


c-KIT Inhibitor, Tyrosine Kinase KIT Gene Inhibitor, Stem Cell Factor Receptor Inhibitor, C-kit Gene Mutation, Stem Cell Factor Receptor, Stem Cell Factor

  • Indications
  1. Gastrointestinal Stromal Tumor (c-KIT+, adjuvant after complete tumor resection)
  • Mechanism
  1. Stem Cell Factor (SCF, tumor-associated antigen Mast Cell factor)
    1. SCF is expressed during Embryogenesis, and binds and activates C-Kit Tyrosine Kinase Receptors
    2. SCF is a growth factor for multiple cell types (esp. hematopoietic cells)
      1. Mast Cell differentiation and function
      2. Melanocytes
  2. C-Kit Cell Surface Protein (Stem Cell Factor Receptor or SCFR)
    1. C-Kit is a transmembrane Protein and receptor Tyrosine Kinase, activated on binding by Stem Cell Factor (SCF)
    2. C-Kit is an important factor in the regulation of cell differentiation and proliferation
    3. C-Kit is overexpressed in some solid and Hematologic Cancers (e.g. GI stromal tumors)
  3. C-Kit Inihibitors
    1. Inhibit specific C-Kit mutations, overexpressed in certain tumors, reducing their cell proliferation
  • Medications
  • c-KIT Inhibitors
  1. See BCR-ABL Inhibitor
  2. Nilotinib (Tasigna)
    1. Binds and stabilizes inactive ABL Protein kinase, with greater potency and less resistance than Imatinib
    2. Also a Platelet-derived growth factor receptor Antagonist (PDGF-R inhibitor) and c-KIT Inhibitor
    3. Risk of Prolonged QT, myelosuppression, Hemorrhage, Pneumonia, Pancreatitis, Peripheral Arterial Disease progression
    4. Avoid with moderate-strong CYP3A Inhibitors and Inducers
    5. Take on empty Stomach (increased absorption and toxicity risk with food)
  3. Imatinib mesylate (Gleevec)
    1. BCR-ABL Inhibitor and also a Stem Cell Factor (SCF) and c-KIT Inhibitor (Tyrosine Kinase KIT Gene Inhibitor)
    2. Also a Platelet-derived growth factor inhibitor (PDGF Inhibitor)
    3. Risk of edema, Tumor Lysis Syndrome, myelosuppression, hepatotoxicity, bleeding, Stevens Johnson Syndrome, pseudoporphyria
    4. Avoid with moderate-strong CYP3A Inhibitors and Inducers
    5. Increases Warfarin levels and INR, and increases Acetaminophen levels
    6. Also approved in children for ALL (Philadelphia Chromosome positive)
    7. Decreased dosing in renal dysfunction