title: The development of agents targeting the BCR-ABL tyrosine kinase as Philadelphia chromosome-positive acute lymphoblastic leukemia treatment.
abstract: In Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), the BCR-ABL translocation is the main transforming event; consequently, it is targeted by ABL-tyrosine kinase inhibitors (TKIs), the first of which to be identified was imatinib mesylate. There are now four newer TKIs, three so-called second-generation inhibitors and one third generation inhibitor, all of which are more potent than imatinib in in vitro assays. Areas covered: This paper reviews the current knowledge on the function of BCR-ABL. Furthermore, this paper highlights the impact of this knowledge on the development of a targeted therapy approach in Ph+ALL and the obstacles for the successful treatment with these drugs. Expert opinion: Identifying key components involved in disease pathogenesis may lead to new approaches that might overcome resistance mediated to the BCR-ABL TKIs. In a near future, the authors believe that monoclonal antibodies and immunotherapy should also be combined with TKIs and up-front chemotherapy for the successful treatment of ALL.
authors.affiliation: a Hematology Department , Hospices Civils de Lyon, Lyon-Sud Hospital , Pierre Bénite , France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.affiliation: a Hematology Department , Hospices Civils de Lyon, Lyon-Sud Hospital , Pierre Bénite , France.
authors.forename: Maël
authors.initials: M
authors.lastname: Heiblig
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: Acute lymphoblastic leukemia; Philadelphia chromosome; chemotherapy; resistance; tyrosine kinase inhibitors