Tyrosine kinase inhibitors (-ibs)

• resistance is conferred by mutations in kinase domains that prevent binding of the inhibitors

• imatinib is our poster child—it is the only targeted agent that is perfect

  • targets

    • BCR-ABL fusion protein, the primary culprit in CML

    • c-KIT, which is mutated in gastrointestinal stromal tumors (GIST), a rare sarcoma-type tumor in GI tract that can metastasize and kill people

  • toxicity: fluid retention

  • this will be asked on every exam because people are so proud of it

• erlotinib, gefitinib

  • target: EGFR

  • toxicity: horrible rash, like bad acne, because it targets a growth factor in the skin

  • simple view of EGFR pathway: EGFR is overexpressed or constitutively activated in many solid tumors. Ras gets turned on and cells overproliferate

  • uses

    • EGFR inhibitors have very little activity as single agents, except in bronchoalveolar carcinoma (BAC), the lung cancer that happens in non-smokers

    • FDA-approved for 2^nd- or 3^rd-line therapy in NSCL ca, colorectal ca

    • can sensitize cells to chemotherapy and radiation and improves XRT results in head and neck ca

• broad-spectrum kinase inhibitors: sorafinib, sunitinib

  • targets: VEGFR, PDGFR

  • toxicity: hypertension because VEGF is an important growth factor for endothelial cells

  • higher VEGF expression correlates with poorer outcome in many cancers

  • uses

    • renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), which are particularly vascular tumors

    • in these diseases, they induce disease stabilization and this is correlated with increased survival (slight—say, 2 months)

Category: Pharmacology Notes