Resistance to imatinib in chronic myeloid leukemia and therapeutic approaches to circumvent the problem.
The majority of patients with chronic phase chronic myeloid leukaemia (CP-CML) treated with imatinib achieves cytogenetic disease remission. Molecular monitoring for residual disease has prognostic significance: rising BCR-ABL levels may provide earliest indication that a patient has become resistant to treatment. The emergence of resistance to imatinib has dampened the enthusiasm for this drug. The most common cause of resistance is the selection of leukemic clones mutated in ABL kinase domain due to amino acid substitutions with prevention of appropriate binding of the drug. Amplification and over-expression of BCR-ABL, acquired cytogenetic aberrations and modulation of drug efflux or influx transporters have been reported. These observations have established the rationale for the creation of new compounds that have been explored in clinical trials. This review will discuss the underlying mechanisms of imatinib-resistance and new strategies to avoid and overcome this phenomenon.
Breccia
Massimo
M
Department of Human Biotechnology and Hematology, Via Benevento 6, 00161 Roma, Italy. breccia@bce.uniroma1.it
Alimena
Giuliana
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012074:Remission Induction / Q000379:methods
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate