Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia.
Through sequencing analysis of blood or bone marrow samples from patients with chronic myeloid leukemia, we identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups-those that alter amino acids that directly contact imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for imatinib binding. Distinct mutations conferred varying degrees of imatinib resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression. Multiple independent mutant clones were detected in a subset of relapsed cases. Our data support a clonal selection model of preexisting BCR-ABL mutations that confer imatinib resistance.
Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Neil P
NP
Shah
John M
JM
Nicoll
Bhushan
B
Nagar
Mercedes E
ME
Gorre
Ronald L
RL
Paquette
John
J
Kuriyan
Charles L
CL
Sawyers
D000483:Alleles; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001549:Benzamides; D002986:Clinical Trials as Topic; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008958:Models, Molecular; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D012008:Recurrence; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl