Sources of therapeutic failure

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