A view on drug resistance in cancer

Nature. 2019 Nov;575(7782):299-309. doi: 10.1038/s41586-019-1730-1. Epub 2019 Nov 13.


The problem of resistance to therapy in cancer is multifaceted. Here we take a reductionist approach to define and separate the key determinants of drug resistance, which include tumour burden and growth kinetics; tumour heterogeneity; physical barriers; the immune system and the microenvironment; undruggable cancer drivers; and the many consequences of applying therapeutic pressures. We propose four general solutions to drug resistance that are based on earlier detection of tumours permitting cancer interception; adaptive monitoring during therapy; the addition of novel drugs and improved pharmacological principles that result in deeper responses; and the identification of cancer cell dependencies by high-throughput synthetic lethality screens, integration of clinico-genomic data and computational modelling. These different approaches could eventually be synthesized for each tumour at any decision point and used to inform the choice of therapy.

Publication types

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

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Drug Resistance, Neoplasm / immunology
  • Drug Resistance, Neoplasm / physiology*
  • Humans
  • Models, Biological
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Tumor Microenvironment


  • Antineoplastic Agents