title: Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain.
abstract: The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph+) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph+ patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317.
authors.affiliation: Institute of Hematology and Medical Oncology L. e A. Seràgnoli, University of Bologna, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Colarossi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gnani
authors.forename: Fausto
authors.initials: F
authors.lastname: Castagnetti
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Rosti
authors.forename: Costanza
authors.initials: C
authors.lastname: Bosi
authors.forename: Stefania
authors.initials: S
authors.lastname: Paolini
authors.forename: Michela
authors.initials: M
authors.lastname: Rondoni
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Piccaluga
authors.forename: Francesca
authors.initials: F
authors.lastname: Palandri
authors.forename: Panagiota
authors.initials: P
authors.lastname: Giannoulia
authors.forename: Giulia
authors.initials: G
authors.lastname: Marzocchi
authors.forename: Simona
authors.initials: S
authors.lastname: Luatti
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Testoni
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Daniela
authors.initials: D
authors.lastname: Cilloni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012008:Recurrence; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D003062:Codon; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib