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