Impact of Membrane Drug Transporters on Resistance to Small-Molecule Tyrosine Kinase Inhibitors.
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.
['Neul|Claudia|C|', 'Schaeffeler|Elke|E|', 'Sparreboom|Alex|A|', 'Laufer|Stefan|S|', 'Schwab|Matthias|M|', 'Nies|Anne T|AT|']
D000818:Animals D004351:Drug Resistance D044127:Epigenesis, Genetic D014644:Genetic Variation D006801:Humans D054990:Idiopathic Pulmonary Fibrosis D026901:Membrane Transport Proteins D009369:Neoplasms D047428:Protein Kinase Inhibitors D011505:Protein-Tyrosine Kinases
tyrosine kinase inhibitors clinical trials drug resistance interindividual variability ABC transporters SLC transporters pharmacogenomics