Multi-scale Predictions of Drug Resistance Epidemiology Identify Design Principles for Rational Drug Design

Cell Rep. 2020 Mar 24;30(12):3951-3963.e4. doi: 10.1016/j.celrep.2020.02.108.

Abstract

Rationally designing drugs that last longer in the face of biological evolution is a critical objective of drug discovery. However, this goal is thwarted by the diversity and stochasticity of evolutionary trajectories that drive uncertainty in the clinic. Although biophysical models can qualitatively predict whether a mutation causes resistance, they cannot quantitatively predict the relative abundance of resistance mutations in patient populations. We present stochastic, first-principle models that are parameterized on a large in vitro dataset and that accurately predict the epidemiological abundance of resistance mutations across multiple leukemia clinical trials. The ability to forecast resistance variants requires an understanding of their underlying mutation biases. Beyond leukemia, a meta-analysis across prostate cancer, breast cancer, and gastrointestinal stromal tumors suggests that resistance evolution in the adjuvant setting is influenced by mutational bias. Our analysis establishes a principle for rational drug design: when evolution favors the most probable mutant, so should drug design.

Keywords: drug resistance; predictive evolution; stochastic dynamics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Animals
  • Drug Design*
  • Drug Development
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Epidemiologic Studies*
  • Evolution, Molecular
  • Humans
  • Imatinib Mesylate / pharmacology
  • Imatinib Mesylate / therapeutic use
  • Mice
  • Models, Biological
  • Mutation / genetics
  • Proto-Oncogene Proteins c-abl / genetics
  • Salts / chemistry
  • Stochastic Processes

Substances

  • Salts
  • Imatinib Mesylate
  • ABL1 protein, human
  • Proto-Oncogene Proteins c-abl