Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy.

摘要: Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly advanced disease. We sought to determine underlying mechanisms. Sixty-six CML myeloid blast crisis (n = 33), lymphoid 2), accelerated phase 16), 13), BCR-ABL-positive acute lymphoblastic 2) resistant were investigated. Median duration therapy was 148 days (range 6-882). Patients evaluated for genomic amplification BCR-ABL, overexpression transcripts, clonal karyotypic evolution, mutations binding site domain. Results as follows: (1) levels not significantly changed at time but 7/55 showed >10-fold increase levels; (2) found 2/32 fluorescence situ hybridization; (3) additional chromosomal aberrations observed 19/36 patients; (4) point ABL domain resulting reactivation detected 23/66 patients. In conclusion, although heterogeneous development challenging, fact that active many suggests chimeric oncoprotein remains good target. However, evolution are more likely have BCR-ABL-independent mechanisms resistance. The observations warrant trials combining other agents.