title: Choosing the best second-line tyrosine kinase inhibitor in imatinib-resistant chronic myeloid leukemia patients harboring Bcr-Abl kinase domain mutations: how reliable is the IC₅₀?
abstract: Development of drug resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients is often accompanied by selection of point mutations in the kinase domain (KD) of the Bcr-Abl oncoprotein, where imatinib binds. Several second-generation tyrosine kinase inhibitors (TKIs) have been designed rationally so as to enhance potency and retain the ability to bind mutated forms of Bcr-Abl. Since the preclinical phase of their development, most of these inhibitors have been tested in in vitro studies to assess their half maximal inhibitory concentration (IC₅₀) for unmutated and mutated Bcr-Abl-that is, the drug concentration required to inhibit the cell proliferation or the phosphorylation processes driven by either the unmutated or the mutated forms of the kinase. A number of such studies have been published, and now that two inhibitors-dasatinib and nilotinib-are available for the treatment of imatinib-resistant cases, it is tempting for clinicians to reason on the IC₅₀ values to guess, case by case, which one will work best in patients harboring specific Bcr-Abl KD mutations. Here, we discuss the pros and cons of using this approach in TKI selection.
authors.affiliation: Department of Haematology/Oncology, L. e A. Serígnoli, University of Bologna, Bologna, Italy. simona.soverini@tin.it
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Rosti
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D002986:Clinical Trials as Topic; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D017354:Point Mutation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib