Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back

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Abstract
Cancer research within the last decades elucidated signaling pathways and identified genes and proteins that lead or contribute to malignant transformation of a cell. Discovery of the Bcr–Abl oncoprotein as the molecular abnormality causing chronic myeloid leukemia (CML) paved the way for the development of a targeted anticancer therapy. The substantial activity of imatinib mesylate (STI571, Glivec) in CML and Philadelphia (Ph)-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) changed the therapeutic approach to Ph+ leukemia and rang the bell for a new era of anticancer treatment. However, when the phenomenon of relapse occurred despite continued imatinib treatment, we had to learn the lesson that imatinib can select for a resistant disease clone. If such a clone still depends on Bcr–Abl, it either carries a BCR–ABL point mutation that prevents binding of the drug or expresses the fusion protein at high levels. Alternatively, leukemia cells that harbor secondary genetic alterations resulting in Bcr–Abl-independent proliferation are selected for their growth advantage in the presence of imatinib. Point mutations in the BCR–ABL kinase domain prevent binding of imatinib but still allow binding of ATP, thus retaining Bcr–Abl kinase activity. Mutated BCR–ABL is frequently detected in cases of imatinib-resistant Ph+ leukemia and therefore represents the main challenge for the investigation of alternative strategies to either overcome resistance or to prevent the emergence of a resistant leukemic clone.