Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia

Key Points The structural basis for imatinib resistance in chronic myeloid leukaemia (CML) involves the emergence of imatinib-resistant BCR-ABL point mutations; mutations are usually those that impair drug binding. More than 50 different BCR-ABL mutations have been identified in patients with imatinib-resistant CML and through random mutagenesis assays. Different imatinib-resistant BCR-ABL point mutants can have different transforming potentials in cells and different prognostic outcomes. Methods to predict imatinib-resistant BCR-ABL mutants include PCR-based screening assays, such as the highly sensitive allele-specific oligonucleoside (ASO)-PCR method, and the denaturing high-performance liquid chromatography (D-HPLC)-based assay. Imatinib-resistant BCR-ABL point mutations have been found to pre-exist in newly diagnosed patients with CML, as well as be acquired owing to selective pressure of imatinib. Furthermore, imatinib fails to deplete leukaemic stem cells. New BCR-ABL inhibitors in clinical trials include ABL inhibitors (nilotinib), dual Src family and ABL kinase inhibitors (bosutinib, INNO-404 and AZD0530), non-ATP competitive inhibitors of BCR-ABL (ON012380) and Aurora kinase inhibitors (MK-0457 and PHA-739358). The dual Src and ABL inhibitor dasatinib has recently been approved by the US Food and Drug Administration for the treatment of patients with CML or Philadelphia chromosome positive acute lymphoblastic leukaemia resistant or intolerant to imatinib. BCR-ABL point mutants resistant to the second generation inhibitors nilotinib and dasatinib have been identified through cell-based resistance screens. Strategies to circumvent the emergence of resistance include combination therapy using inhibitors of BCR-ABL and other targets. Imatinib is a highly effective treatment for chronic myeloid leukaemia. However, patients often develop resistance to this ABL kinase inhibitor. This Review discusses second generation inhibitors of ABL and other signalling pathways that might help circumvent imatinib resistance. Imatinib, a small-molecule ABL kinase inhibitor, is a highly effective therapy for early-phase chronic myeloid leukaemia (CML), which has constitutively active ABL kinase activity owing to the expression of the BCR-ABL fusion protein. However, there is a high relapse rate among advanced- and blast-crisis-phase patients owing to the development of mutations in the ABL kinase domain that cause drug resistance. Several second-generation ABL kinase