Author(s): Soverini S, Rosti G, Iacobucci I, Baccarani M, Martinelli G
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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.
This article was published in Oncologist
and referenced in Journal of Clinical & Experimental Pathology