Targeted drugs in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between the long arms of the chromosomes 9 and 22 t(9;22)(q34;q11). This translocation creates two new genes, BCR-ABL on the 22q- (Ph chromosome) and the reciprocal ABL-BCR on 9q-. The BCR-ABL gene encodes for a 210-kD protein with deregulated tyrosine kinase (TK) activity, which is crucial for malignant transformation in CML. The recognition of the BCR-ABL gene and corresponding protein led to the synthesis of small-molecule drugs, designed to interfere with BCR-ABL tyrosine kinase activation by competitive binding at the ATP-binding site. The first tyrosine kinase inhibitor (TKI), introduced into clinical practice in 1998, was imatinib mesylate. Imatinib became the first choice drug in chronic phase CML, because of its high efficacy, low toxicity and ability to maintain durable hematological and cytogenetic responses. However, approximately 20-25% of patients initially treated with imatinib will need alternative therapy, due to drug resistance, which is often caused by the appearance of clones expressing mutant forms of BCR-ABL. Second-generation TKIs have provided new therapeutic option for the patients resistant to imatinib. Dasatinib is the first, second-generation TKI, approved in the US and European Union for the treatment of CML patients with imatinib resistance or intolerance. This drug is a dual SRC-ABL kinase inhibitor, active in most clinically relevant BCR-ABL mutations, except highly resistant T315I. Other second-generation TKIs include nilotinib, bosutinib and INNO 406. Apart from TKIs, the promising group of molecules is inhibitors of Aurora family of serine-threonine kinases. One of these molecules, MK0457, has entered clinical trials, and initial reports indicate that this compound could be active in disease associated with T315I mutation. Thus, wide spectrum of new agents, with different mode of action, is currently in clinical development for CML. It is likely that combination therapy will be the best therapeutic strategy in the future.