Impact of Membrane Drug Transporters on Resistance to Small-Molecule Tyrosine Kinase Inhibitors

Trends Pharmacol Sci. 2016 Nov;37(11):904-932. doi: 10.1016/ Epub 2016 Sep 19.


Small-molecule inhibitors of tyrosine kinases (TKIs) are the mainstay of treatment for many malignancies and represent novel treatment options for other diseases such as idiopathic pulmonary fibrosis. Twenty-five TKIs are currently FDA-approved and >130 are being evaluated in clinical trials. Increasing evidence suggests that drug exposure of TKIs may significantly contribute to drug resistance, independently from somatic variation of TKI target genes. Membrane transport proteins may limit the amount of TKI reaching the target cells. This review highlights current knowledge on the basic and clinical pharmacology of membrane transporters involved in TKI disposition and their contribution to drug efficacy and adverse drug effects. In addition to non-genetic and epigenetic factors, genetic variants, particularly rare ones, in transporter genes are promising novel factors to explain interindividual variability in the response to TKI therapy.

Keywords: ABC transporters; SLC transporters; clinical trials; drug resistance; interindividual variability; pharmacogenomics; tyrosine kinase inhibitors.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Resistance
  • Epigenesis, Genetic
  • Genetic Variation
  • Humans
  • Idiopathic Pulmonary Fibrosis / drug therapy
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism


  • Membrane Transport Proteins
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases