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.
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.
Soverini
Simona
S
Institute of Hematology and Medical Oncology L. e A. Seràgnoli, University of Bologna, Bologna, Italy.
Colarossi
Sabrina
S
Gnani
Alessandra
A
Castagnetti
Fausto
F
Rosti
Gianantonio
G
Bosi
Costanza
C
Paolini
Stefania
S
Rondoni
Michela
M
Piccaluga
Pier Paolo
PP
Palandri
Francesca
F
Giannoulia
Panagiota
P
Marzocchi
Giulia
G
Luatti
Simona
S
Testoni
Nicoletta
N
Iacobucci
Ilaria
I
Cilloni
Daniela
D
Saglio
Giuseppe
G
Baccarani
Michele
M
Martinelli
Giovanni
G
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
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