title: Chronic myeloid leukemia: advances in understanding disease biology and mechanisms of resistance to tyrosine kinase inhibitors.
abstract: The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) remains a flagship for molecularly targeted therapy in cancer. This focused review highlights critical elements of the underlying biology of CML and provides a summary of the molecular mechanisms that lead to TKI resistance: BCR-ABL1 mutation-based resistance and therapy escape through alternative pathway activation despite inhibition of BCR-ABL1 tyrosine kinase activity. We direct attention to the most current manifestations of these issues, including emergence of pan-TKI-resistant BCR-ABL1 compound mutants, new strategies for identification and therapeutic targeting of alternative pathways, and the exciting, controversial topic of cessation of TKI therapy leading to durable treatment-free remissions for a subset of patients. Further gains in our understanding of the biology of Philadelphia chromosome-positive (Ph-positive) leukemia and mechanisms of resistance to BCR-ABL1 TKIs will benefit patients and also provide a blueprint for similar discovery in other cancers.
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl