Chronic myelogenous leukemia (CML): resistance to tyrosine kinase inhibitors.

Chronic myelogenous leukemia (CML) is attributed to the chromosomal translocation t(9;22)(q34;q11), yielding the Philadelphia (Ph) chromosome. This translocation generates a fusion gene that encodes BCR-ABL, a constitutively active protein tyrosine kinase. Signal transduction pathways stimulated by BCR-ABL kinase activity promote cell survival and proliferation while inhibiting apoptosis [1]. The discovery of the BCR-ABL-mediated pathogenesis of CML provided the rationale for the design of an inhibitory agent that targets BCR-ABL kinase activity [2]. Imatinib mesylate (Glivec , Novartis, Basel, Switzerland) is a selective inhibitor of ABL and its derivative BCR-ABL, as well as other type III tyrosine kinases. It is effective as a single agent in the treatment of CML patients, with the most encouraging results seen in patients in chronic phase (CP) disease. A minority of CML patients in CP and a substantial proportion in advanced disease phases are either initially refractory to imatinib treatment or lose imatinib sensitivity over time and experience relapse. Resistance to imatinib in patients has been associated with a heterogeneous array of mechanisms that range from non-specific multi-drug resistance to BCR-ABL inherent genetic alterations. The most frequently identified mechanism of acquired imatinib resistance is BCR-ABL kinase domain point mutations that impair imatinib binding, either by interfering with an imatinib binding site or by stabilising a BCR-ABL conformation with reduced affinity to imatinib [3].