title: Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia.
abstract: Beginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collectively, these drugs target most resistant BCR-ABL mutants, with the exception of BCR-ABL(T315I). A third wave of advances is now cresting in the form of ABL kinase inhibitors whose target profile encompasses BCR-ABL(T315I). The leading third-generation clinical candidate for treatment-refractory CML, including patients with the T315I mutation, is ponatinib (AP24534), a pan-BCR-ABL inhibitor that has entered pivotal phase 2 testing. A second inhibitor with activity against the BCR-ABL(T315I) mutant, DCC-2036, is in phase 1 clinical evaluation. We provide an up-to-date synopsis of BCR-ABL signaling pathways, highlight new findings on mechanisms underlying BCR-ABL mutation acquisition and disease progression, discuss the use of nilotinib and dasatinib in a first-line capacity, and evaluate ponatinib, DCC-2036, and other ABL kinase inhibitors with activity against BCR-ABL(T315I) in the development pipeline.
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, USA. oharet@ohsu.edu
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.forename: Michael W N
authors.initials: MW
authors.lastname: Deininger
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D015507:Drugs, Investigational; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D058990:Molecular Targeted Therapy; D009154:Mutation; D011724:Pyridazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D007093:Imidazoles; D011724:Pyridazines; D011743:Pyrimidines; D013844:Thiazoles; C545373:ponatinib; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib