title: Development of an effective therapy for chronic myelogenous leukemia.
abstract: Targeted small-molecule drugs have revolutionized treatment of chronic myeloid leukemia (CML) during the last decade. These agents interrupt a constitutively active BCR-ABL, the causative agent for CML, by interfering with adenosine 5' triphosphate-dependent ABL tyrosine kinase. Although the efficacy of tyrosine kinase inhibitors (TKIs) has resulted in overall survival of greater than 90%, TKIs are not curative. Moreover, no currently approved TKIs are effective against the T315I BCR-ABL variant. However, a new generation of TKIs with activity against T315I is on the horizon. We will highlight the clinical utility of historical CML therapeutics, those used today (first- and second-generation TKIs), and discuss treatment modalities that are under development. Recent advances have illuminated the complexity of CML, especially within the marrow microenvironment. We contend that the key to curing CML will involve strategies beyond targeting BCR-ABL because primitive human CML stem cells are not dependent on BCR-ABL. Ultimately, drug combinations or exploiting synthetic lethality may transform responses into definitive cures for CML.
authors.affiliation: Departments of Pharmacology and Toxicology, College of Pharmacy, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Woessner
authors.forename: Carol S
authors.initials: CS
authors.lastname: Lim
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D019008:Drug Resistance, Neoplasm; D006801:Humans; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases