The influence of subclonal resistance mutations on targeted cancer therapy

Nat Rev Clin Oncol. 2016 Jun;13(6):335-47. doi: 10.1038/nrclinonc.2015.175. Epub 2015 Oct 20.


Clinical oncology is being revolutionized by the increasing use of molecularly targeted therapies. This paradigm holds great promise for improving cancer treatment; however, allocating specific therapies to the patients who are most likely to derive a durable benefit continues to represent a considerable challenge. Evidence continues to emerge that cancers are characterized by extensive intratumour genetic heterogeneity, and that patients being considered for treatment with a targeted agent might, therefore, already possess resistance to the drug in a minority of cells. Indeed, multiple examples of pre-existing subclonal resistance mutations to various molecularly targeted agents have been described, which we review herein. Early detection of pre-existing or emerging drug resistance could enable more personalized use of targeted cancer therapy, as patients could be stratified to receive the therapies that are most likely to be effective. We consider how monitoring of drug resistance could be incorporated into clinical practice to optimize the use of targeted therapies in individual patients.

Publication types

  • Review

MeSH terms

  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Genes, erbB-1 / genetics
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Signaling System / drug effects
  • Molecular Targeted Therapy / methods
  • Mutation / drug effects
  • Mutation / genetics*
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-kit / antagonists & inhibitors


  • BCR-ABL1 fusion protein, human
  • ARG tyrosine kinase
  • EGFR protein, human
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-kit
  • Fusion Proteins, bcr-abl
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase Kinases