Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia.
The introduction of selective tyrosine-kinase inhibitors (TKIs) for the treatment of chronic myeloid leukaemia has changed patient outcome and, consequently, management of this disease. Imatinib is now the treatment of choice for most newly diagnosed patients. Excellent responses, in terms of symptom control and haematological parameters, are usually obtained. However, failure to completely eradicate leukaemic cells and the escape of these cells from previous control has led to an intensive search for the mechanisms of resistance and subsequent treatments by which to overcome this resistance. Up to now, there has been considerable focus on the role of ABL-kinase-domain mutations as mediators of resistance to imatinib, thereby encouraging the development of a second generation of TKIs capable of inhibiting these mutant proteins. However, studies have increasingly shown that these mutations do not account for all cases of resistance and have a negligible role in the inability of TKIs to eradicate residual disease in patients who are good responders. More recently, attention has turned to the relative roles of drug bioavailability and drug efflux and drug influx proteins in the development of resistance to imatinib. This review is the first of two papers and discusses imatinib resistance and its potential causes. The second paper will focus on the assessment and subsequent management of patients with less than optimum responses to imatinib.
Apperley
Jane F
JF
Department of Haematology, Imperial College, Hammersmith Hospital, London, UK. j.apperley@imperial.ac.uk
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl