Cytogenetic and molecular mechanisms of resistance to imatinib.
Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (Gleevec) (formerly STI571) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs in patients with chronic phase (CP) and advanced disease. A cohort of 72 patients with CML in myeloid blast crisis (BC) (n = 34), lymphoid BC (n = 2), accelerated phase (AP) (n = 16), CP (n = 18), and BCR-ABL(+) acute lymphoblastic leukemia (ALL) (n = 2) resistant to imatinib were investigated. Median levels of BCR-ABL transcripts, determined by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), were not significantly changed at the time of resistance, but seven of 55 patients showed a greater than 10-fold increase in BCR-ABL levels. Genomic amplification of BCR-ABL was found in two of 32 patients evaluated by fluorescence in situ hybridization (FISH). Additional chromosomal aberrations were observed in 19 of 36 patients and point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 29 of 72 patients. Resistance may be caused by BCR-ABL-independent or BCR-ABL-dependent mechanisms. A thorough evaluation of resistant cases is required to suggest therapeutic measures in the individual case. Clonal selection of resistant cells harboring a BCR-ABL mutation might be reversed by stopping imatinib therapy and switching to chemotherapy. Combination therapy from the start of treatment to reduce the frequency of resistance is currently being evaluated with several drugs.
Hochhaus
Andreas
A
III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany.
D001549:Benzamides; D002869:Chromosome Aberrations; D002999:Clone Cells / Q000473:pathology; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D016313:Genes, abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D017354:Point Mutation; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012334:RNA, Neoplasm / Q000032:analysis; D016896:Treatment Outcome
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012334:RNA, Neoplasm; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl