title: Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance.
abstract: Given its relative rarity, it may at first seem surprising that chronic myeloid leukemia (CML) has garnered so much attention over the last decade. Yet, the advances in molecular pathogenesis that have been derived from studying this leukemia have clearly benefited all of oncology. Moreover, the strides in drug design and development that have also ensued around CML have given rise to what others have called a molecular revolution in cancer therapy. While a majority of patients with chronic phase CML (CP-CML) have an excellent durable response to imatinib (Gleevec, Novartis, Basel, Switzerland), a clear minority will unfortunately have signs of primary or secondary resistance to therapy. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the biology of drug trafficking into and out of cells, epigenetic control of cellular processes, alterations in enzymatic structures, and the rational structural-based design of small molecule enzyme inhibitors. This review will describe the efforts at understanding the pathogenesis of imatinib resistance and the molecular rationale for the development of second- and now third-generation therapies for patients with CML.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Bixby
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use; D044127:Epigenesis, Genetic; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000145:classification / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016879:Salvage Therapy; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D015507:Drugs, Investigational; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl