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  • Review Article
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Flying under the radar: the new wave of BCR–ABL inhibitors

Key Points

  • Single-point mutations within the kinase domain of BCR–ABL constitute the most frequent cause of acquired resistance to ABL kinase inhibitors in patients with chronic myeloid leukaemia (CML) receiving imatinib therapy.

  • BCRABL mutations affect direct drug contact sites and sites involved in conformational changes required for imatinib binding.

  • Second-generation ABL-kinase inhibitors such as nilotinib and dasatinib are efficacious after imatinib failure but, like imatinib, lack activity against the T315I mutation. Dasatinib is also a potent inhibitor of the SRC family of kinases (SFKs) whose overexpression has been implicated in cases of imatinib resistance.

  • BCRABL mutations conferring resistance to nilotinib and dasatinib have been detected in mutagenesis assays and in clinical samples from patients with CML.

  • A new generation of BCR–ABL inhibitors comprises agents with different mechanisms of action including novel dual ABL/SFK inhibitors (for example, bosutinib, INNO-406, AZD0530 and 2,6,9-trisubstituted purine derivatives); non-ATP-competitive inhibitors (GNF-2 and ON012380); and Aurora kinase inhibitors (MK-0457, VE-465, KW2449 and PHA-739358).

  • Clinical studies are underway to evaluate the safety and efficacy of the Aurora kinase inhibitor MK-0457 and the multikinase inhibitor XL228 in patients with CML expressing the BCRABL1T315I mutation.

  • Extrapolating strategies used in the development of BCR–ABL inhibitors for CML will undoubtedly abet researchers in designing and optimizing efficacious targeted therapies for other human cancers such as non-small cell lung cancer driven by mutant alleles of epidermal growth factor receptor (EGFR) or gastrointestinal stromal tumours expressing mutant KIT.

  • The development of any tyrosine kinase inhibitor must be inextricably linked to a sound and meticulous understanding of the mechanisms of resistance associated with its use.

Abstract

The introduction of the BCR–ABL kinase inhibitor imatinib mesylate (Gleevec; Novartis) revolutionized the treatment of chronic myeloid leukaemia (CML). However, most patients with CML receiving imatinib still harbour molecular residual disease and some develop resistance associated with ABL kinase domain mutations. The second-generation BCR–ABL inhibitors nilotinib (Tasigna; Novartis) and dasatinib (Sprycel; Bristol–Myers Squibb) have shown significant activity after imatinib failure in clinical trials, but still face similar obstacles to imatinib, including negligible activity against the frequent BCR–ABL T315I mutation and modest effects in advanced phases of CML. Various medicinal chemistry efforts, in part aided by structural studies of the ABL kinase–imatinib complex have resulted in the synthesis of a new generation of BCR–ABL inhibitors, some of which have shown encouraging preliminary activity in clinical trials, including against T315I mutants. Here, we discuss these emerging therapies, which have the potential to improve the outcome of patients with CML.

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Figure 1: Oncogenic signalling of BCR–ABL kinase.
Figure 2: Structural organization of BCR–ABL and SFKs.
Figure 3: Different modes of BCR–ABL binding.

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Acknowledgements

A.Q.-C. is perennially indebted to E. Schiele, J. Lado-Abeal and L. Hayward for their ceaseless inspiration, and to D. L. Gibbons for his unremitting remaking/remodelling/rethinking. W.H.: “I understand the fury in your words, but not the words”.

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Correspondence to Alfonso Quintás-Cardama.

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J.C. and H.K. receive research grant support from Novartis and Bristol–Myers Squibb.

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DATABASES

OMIM

Analplastic large-cell lymphoma

chronic myeloid leukaemia

GIST

lung cancer

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M. D. Anderson Leukemia Department

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Quintás-Cardama, A., Kantarjian, H. & Cortes, J. Flying under the radar: the new wave of BCR–ABL inhibitors. Nat Rev Drug Discov 6, 834–848 (2007). https://doi.org/10.1038/nrd2324

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