Sources of therapeutic failure

From Santa Fe Institute Events Wiki

The field of cancer drug resistance is pretty diverse, with causes ascribed to:

  • Hypoxia
    • if oxygen can't get to the cells, drugs might not either
    • Oxygen is necessary for radiotherapy response
  • Lack of the drug target (e.g., ER- cells in tamoxifen therapy)
  • Density of the microenvironment - neoplasms and their surrounding matrix are often dense, and may impede drug diffusion.
  • Upregulation of eflux pumps
  • Methylation changes (not sure which yet)
  • Genetic changes:
    • Gleevec (Imatinib): BCR-ABL mutations
    • 5-Flurouracil: TYMS amplification
    • Gefitinib:
      • EGFR mutation
      • MET amplification
    • Anti-angiogenic therapy
      • Switching expression to a new angiogenic factor not targeted by the drug
      • Growth along existing blood vessels
    • Tamoxifen (and other selective estrogen modulating drugs)
      • Loss of the estrogen receptor (domination by a clone that does not require ER)
      • Upregulation of the estrogen receptor
      • Constitutive activation of the estrogen receptor (rare in clinical samples)
      • Mutant, hypersensitive ER