Resistance to tyrosine kinase inhibition therapy for chronic myelogenous leukemia: a clinical perspective and emerging treatment options

Abstract

The development of tyrosine kinase inhibitors (TKIs) has led to extended lifespans for many patients with chronic myelogenous leukemia (CML). However, 20% to 30% of patients fail to respond, respond suboptimally, or experience disease relapse after treatment with imatinib. A key factor is drug resistance. The molecular mechanisms implicated in this resistance include those that involve upregulation or mutation of BCR-ABL kinase and those that are BCR-ABL independent. The clinical consequences of these molecular mechanisms of resistance for disease pathogenesis remain open for debate. This review summarizes the molecular mechanisms and clinical consequences of TKI resistance and addresses the current and future treatment approaches for patients with TKI-resistant CML.

Keywords: BCR-ABL mutations; Molecular mechanisms; T315I.

Figure 1

Schematic Map of Some of the Most Common Amino Acid Substitutions Identified From Clinical Specimens in Patients Resistant to Imatinib. The Stars Highlight Regions Involved in Imatinib Binding. Mutations in Italics Have Been Found to be Single Nucleotide Polymorphismsa Abbreviations: A loop = activation loop; P loop = phosphate-binding loop; SH2 = SRC homology 2; SH3 = SRC homology 3. ^aReproduced with permission of the American Society of Hematology, from Soverini S, et al. Blood 118(5), 2011: 1208–1215, permission conveyed through Copyright Clearance Center, Inc.