Table 1.

Evolutionary origins of selection for drug resistance in cancer

MechanismOrigins
Genetic
  • Selection of preexisting, stochastic mutations in drug response pathway

The “classic” escape route: the inevitable consequence of mutation rates and clone size.
  • Segregation of drug targets in subclones

For targeted therapy. The consequence of genetic variegation.
Epigenetic
  • Quiescent stem cells

An ancient survival trait—“hunkering down” to protect against stress. Evident in bacteria and normal stem cells.
  • Signal block bypass

For targeted therapy. A consequence of signal network complexity, redundancy, and multiplicity of microenvironmental signals. An early evolutionary innovation, as seen in bacteria and yeast.