6533b860fe1ef96bd12c3c02

RESEARCH PRODUCT

Chronic Myelogenous Leukemia: Approaches to Pharmacological Resistance

subject

description

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by the reciprocal t (9:22) chromosomal translocation. This rearrangement produces the socalled Philadelphia chromosome carrying the chimeric Bcr-Abl oncoprotein, p210, responsible of disease progression [1]. Because of its critical role in pathogenesis, the scientific community had focused on targeting Bcr–Abl for treatment of CML. For many years Imatinib (IM), as selective inhibitor of the Tyr-Kinase activity of the oncoprotein, was used to treat CML patients [2]. From 2000 some data relative to IM resistance were available. There are many mechanisms responsible of IM resistance, more often point mutations that cause the progression to blast crisis and death in few months. To circumvent them, more potent TKIs have been subsequently approved [3]. However, another problem arise: these compounds don’t work on all patients because of the different IMresistant mutants of BCR-ABL[4]. Therefore, there is a continous need for new drugs and combinations that could improve responses and survival rates for CML. Moreover, because of the complexity of signalling pathways and the overexpression of many of them on tumour cells, the simultaneous use of different drugs to target alternative signalling may produce an higher therapeutic success accompanied by less toxicity.