title: Pharmacogenetics of small-molecule tyrosine kinase inhibitors: Optimizing the magic bullet.
abstract: Cancer treatment has undergone revolutionary changes during the past decade, as a result of the introduction of tyrosine kinase inhibitors (TKIs) that selectively inhibit growth factor pathways critical for tumor growth. Unexpected toxicity profiles and disappointing response rates to these 'magic bullets' have prompted research to identify markers that can predict toxicity or response to such agents. This review discusses the results of pharmacogenetic studies that have used germline DNA to assess the effects of various polymorphisms on currently available small-molecule TKIs. In these studies, polymorphisms in the EGFR gene (ie, EGFR CA-repeat and -216G>T) have consistently been associated with response to the EGFR-blocking TKIs gefitinib and, to a lesser extent, erlotinib. In addition, results from studies investigating polymorphisms in drug transporting enzymes (ie, ABCB1 1236T>C, 2677G>T/A and 3435C>T, and ABCG2 421C>A) suggest such polymorphisms are relevant for the pharmacokinetics of the TKIs; however, some conflicting findings on these polymorphisms have been published. The clinical impact of polymorphisms in EGFR and in drug transporting enzymes needs to be evaluated and validated in order for these pharmacogenetic markers to be applied successfully to individualize treatment in the clinic.
authors.affiliation: Leiden University Medical Center, Department of Clinical Oncology, PO Box 9600, 2300RC Leiden, the Netherlands. a.j.gelderblom@lumc.nl
authors.forename: Jan
authors.initials: J
authors.lastname: Pander
authors.forename: Henk Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D001549:Benzamides; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D000068877:Imatinib Mesylate; D009363:Neoplasm Proteins / Q000235:genetics*; D010597:Pharmacogenetics; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D000068877:Imatinib Mesylate; D000069347:Erlotinib Hydrochloride; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib