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lüll P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia Cang S; Liu DJ Hematol Oncol 2008[Oct]; 1 (ä): 15Imatinib was the first BCR-ABL-targeted agent approved for the treatment of patients with chronic myeloid leukemia (CML) and confers significant benefit for most patients; however, a substantial number of patients are either initially refractory or develop resistance. Point mutations within the ABL kinase domain of the BCR-ABL fusion protein are a major underlying cause of resistance. Of the known imatinib-resistant mutations, the most frequently occurring involve the ATP-binding loop (P-loop). In vitro evidence has suggested that these mutations are more oncogenic with respect to other mutations and wild type BCR-ABL. Dasatinib and nilotinib have been approved for second-line treatment of patients with CML who demonstrate resistance (or intolerance) to imatinib. Both agents have marked activity in patients resistant to imatinib; however, they have differential activity against certain mutations, including those of the P-loop. Data from clinical trials suggest that dasatinib may be more effective vs. nilotinib for treating patients harboring P-loop mutations. Other mutations that are differentially sensitive to the second-line tyrosine kinase inhibitors (TKIs) include F317L and F359I/V, which are more sensitive to nilotinib and dasatinib, respectively. P-loop status in patients with CML and the potency of TKIs against P-loop mutations are key determinants for prognosis and response to treatment. This communication reviews the clinical importance of P-loop mutations and the efficacy of the currently available TKIs against them.|Animals[MESH]|Antineoplastic Agents/pharmacology/*therapeutic use[MESH]|Benzamides[MESH]|Drug Resistance, Neoplasm/*drug effects[MESH]|Fusion Proteins, bcr-abl/genetics[MESH]|Humans[MESH]|Imatinib Mesylate[MESH]|Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy[MESH]|Mutation[MESH]|Piperazines/pharmacology/*therapeutic use[MESH]|Pyrimidines/pharmacology/*therapeutic use[MESH] |