Harvey's Garden

Tyrosine kinase

2 min read

  • Mechanism of Action
    • TKs are a class of receptors (or cytoplasmic enzymes) with intrinsic enzyme activity.
    • Receptor TKs:
      1. Ligand (e.g., growth factor) binds to the receptor’s extracellular domain.
      2. Causes receptor dimerization.
      3. Dimerization activates the intracellular kinase domains, leading to autophosphorylation of tyrosine residues.
      4. Phosphorylated tyrosines act as docking sites for cytoplasmic signaling proteins containing SH2 (Src Homology 2) domains.
  • Key Signaling Pathways Activated
    • MAP Kinase Pathway (RAS-RAF-MEK-ERK): Primarily mediates cell growth, proliferation, and differentiation.
    • PI3K/Akt/mTOR Pathway: Promotes cell survival, growth, and inhibits apoptosis.
  • High-Yield Ligands & Receptors
    • Insulin → Insulin Receptor
    • Epidermal Growth Factor (EGF) → EGFR
    • Platelet-Derived Growth Factor (PDGF) → PDGFR
    • Fibroblast Growth Factor (FGF) → FGFR
    • Vascular Endothelial Growth Factor (VEGF) → VEGFR
    • HER2 (Human Epidermal Growth Factor Receptor 2) is an important TK receptor that does not require a known ligand for dimerization when overexpressed.
  • Pathology & Key Disease Associations
    • Gain-of-function mutations lead to constitutively active TKs, resulting in uncontrolled cell proliferation and malignancy.
      • Chronic Myeloid Leukemia (CML): Driven by the BCR-ABL fusion gene, which creates a constitutively active cytoplasmic TK.
      • Non-Small Cell Lung Cancer (NSCLC): Often associated with activating mutations in EGFR.
      • Gastrointestinal Stromal Tumors (GIST): Commonly driven by mutations in c-KIT.
      • Breast & Gastric Cancer: Overexpression/amplification of HER2.
    • Loss-of-function mutations are also clinically significant, often leading to immunodeficiency or developmental defects.
      • X-linked Agammaglobulinemia (XLA): Caused by a mutation in the gene for Bruton’s Tyrosine Kinase (BTK), a cytoplasmic TK. This leads to a severe block in B-cell maturation, resulting in an absence of B-cells and immunoglobulins and predisposing patients to recurrent bacterial infections.
  • Pharmacology: TK Inhibitors (TKIs) & Monoclonal Antibodies (mAbs)
    • This is an extremely high-yield area for pharmacology.
    • TKIs (small molecules, end in “-tinib”): Enter the cell and inhibit the intracellular kinase domain.
      • Imatinib: Tx for CML (inhibits BCR-ABL) and GIST (inhibits c-KIT).
      • Erlotinib, Gefitinib: Tx for NSCLC with EGFR mutations.
      • Sunitinib, Sorafenib: Multi-targeted TKIs used in Renal Cell Carcinoma (RCC) and Hepatocellular Carcinoma (HCC).
    • Monoclonal Antibodies (large molecules, end in “-mab”): Bind to the extracellular domain of the receptor or the ligand itself.
      • Trastuzumab: Binds to HER2. Tx for HER2+ breast cancer. Cardiotoxicity is a key side effect.
      • Cetuximab, Panitumumab: Bind to EGFR. Tx for metastatic colorectal cancer (only if KRAS is wild-type) and head & neck cancer.
      • Bevacizumab: Binds to VEGF ligand, preventing it from activating the VEGFR. Tx for colorectal cancer, RCC. Side effects include HTN, bleeding, and impaired wound healing.

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