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, 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 inhibitors have been or are being developed for the treatment of imatinib-resistant CML. Here, we describe the mechanism of action of imatinib in CML, the structural basis of imatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance.
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Paul W. Manley and Sandra W. Cowan-Jacob are employees of Novartis pharma AG, Switzerland. Andreas Hochhaus receives research funding from Novartis, Bristol-Myers Squibb, Wyeth, Merck and Innovive.
- Gatekeeper residue
The gatekeeper is a residue located at the back of the ATP-binding site, the properties of which (size, charge and hydrophobicity) regulate the binding of inhibitors.
- Cap region
A region at the N terminus of wild-type ABL, which has a role in keeping the kinase in an inactive state.
PI3K is a heterodimer that is made up of a regulatory (p85) subunit (which BCR-ABL interacts with), and a catalytic (p110) subunit.
- Focal adhesion
A cell-to-substrate adhesion structure that anchors the ends of actin microfilaments (stress fibres) and mediates strong attachment to the extracellular matrix.
- Cytogenetic remission
Complete cytogenetic remission is the absence of metaphase cells positive for the BCR-ABL rearrangement (or Philadelphia chromosome positive cells). Partial cytogenetic remission is the presence of 35% of metaphase cells positive for the BCR-ABL rearrangement (or Philadelphia chromosome positive cells).
- Haematological remission
Complete haematological remission is the achievement of a normal white blood cell (WBC) and platelet count, and no signs and symptoms of CML. Partial haematological remission is a decrease in the WBC count to less than 50% of pretreatment levels.
- Chronic phase
An early phase of CML characterized by variable duration. Patients often lack symptoms, or are mildly symptomatic; if left untreated, this will progress to an accelerated phase.
- Accelerated phase
Occurs between chronic phase and blast crisis. Characterized by 10–19% myeloblasts and >20% basophils in blood or bone marrow and cytogenetic evolution; increasing splenomegaly, platelet count or white blood cell count also occurs in patients who are unresponsive to treatment.
- Blast phase
The final phase of CML (also known as blast crisis), which is similar to an acute leukaemia (poor prognosis). Characterized by >20% myeloblasts or lymphoblasts in blood or bone marrow.
Swelling of tissues that results from the accumulation of excess lymph fluid.
- Pleural effusion
Accumulation of excess fluid in the fluid-filled space that surrounds the lungs.
- Pulmonary oedema
Accumulation of fluid in the alveoli and interstitial spaces of the lungs.
- Pericardial effusion
Accumulation of fluid inside the sac covering the heart.
- Autoactivation site
Region within the kinase domain activation loop that, when phosphorylated by the kinase itself, results in the activation of the protein.
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Weisberg, E., Manley, P., Cowan-Jacob, S. et al. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 7, 345–356 (2007). https://doi.org/10.1038/nrc2126
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