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  • Review Article
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Pushing the limits of targeted therapy in chronic myeloid leukaemia

Nature Reviews Cancer volume 12, pages 513–526 (2012)Cite this article

Subjects

A Corrigendum to this article was published on 15 November 2012

This article has been updated

Key Points

  • Small-molecule BCR-ABL1 tyrosine kinase inhibitors (TKIs) have fundamentally improved the treatment of chronic myeloid leukaemia (CML) and have become a paradigm for molecularly targeted therapy, but they fail to kill leukaemic stem cells (LSCs).

  • BCR-ABL1-dependent resistance to currently approved TKIs typically involves single point mutations within the BCR-ABL1 tyrosine kinase domain that interfere with drug binding.

  • Third-generation TKIs that comprehensively cover single BCR-ABL1 mutants, including the T315I mutant (BCR-ABL1T315I), are in development. With respect to resistance, these TKIs are vulnerable to certain compound mutations (two or more mutations in the same BCR-ABL1 molecule) in in vitro model systems. The extent to which BCR-ABL1 compound mutation-based resistance tempers the effectiveness of third-generation TKIs in the clinical setting remains to be established.

  • BCR-ABL1-independent TKI resistance occurs despite effective inhibition of BCR-ABL1 kinase activity.

  • CML stem cells may rely on pathways similar to those responsible for BCR-ABL1-independent TKI resistance.

  • Other crucial targets in addition to BCR-ABL1 will probably need to be inhibited in both cases. Candidate pathways include Hedgehog, WNT–β-catenin, PP2A and transforming growth factor-β (TGFβ)–Forkhead box protein O3 (FOXO3A)–BCL-6.

Abstract

Tyrosine kinase inhibitor (TKI) therapy targeting the BCR-ABL1 kinase is effective against chronic myeloid leukaemia (CML), but is not curative for most patients. Minimal residual disease (MRD) is thought to reside in TKI-insensitive leukaemia stem cells (LSCs) that are not fully addicted to BCR-ABL1. Recent conceptual advances in both CML biology and therapeutic intervention have increased the potential for the elimination of CML cells, including LSCs, through simultaneous inhibition of BCR-ABL1 and other newly identified, crucial targets.

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Figure 1: Two independent clinical evaluations of first-line use of nilotinib or dasatinib compared with imatinib for newly diagnosed CML.
Figure 2: A partially overlapping network of BCR-ABL1 kinase domain mutations confer resistance to certain TKIs.
Figure 3: Targeting opportunities in CML cells.

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Change history

  • 15 November 2012

    On page 521 of this article, the passage discussing β-catenin as a regulator of gene expression in chronic myeloid leukaemia should have cited the following article alongside reference 118: Radich, J. P. et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc. Natl Acad. Sci. USA 103, 2794–2799 (2006). This has now been added as reference 168.

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Acknowledgements

The authors thank A. Kohlmann, J. Khorashad and C. A. Eide for assistance with figures and valuable suggestions.

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Authors and Affiliations

  1. Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, 84112, Utah, USA

    Thomas O'Hare, Matthew S. Zabriskie, Anna M. Eiring & Michael W. Deininger

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M.W.D. serves on advisory boards and as a consultant for Bristol–Myers Squibb, ARIAD, and Novartis and receives research funding from Bristol–Myers Squibb, Celgene, Genzyme and YM BioSciences. T.O'H., M.S.Z. and A.M.E. declare no competing financial interests.

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Glossary

Type II conformation

The inactive or closed conformation of ABL1 and BCR-ABL1 to which imatinib is capable of binding.

Type I conformation

The active or open conformation of ABL1 and BCR-ABL1 to which imatinib is incapable of binding.

'Gatekeeper' mutation

A threonine to isoleucine substitution of amino acid 315 in BCR-ABL1 protein that interferes with the binding of imatinib and other tyrosine kinase inhibitors.

SH2 domain

SRC homology 2 domain. A protein domain capable of binding tyrosine phosphorylated sites.

Aggresomes

Areas within the cell that result from the accumulation of protein for disposal. Aggresomes generally form during times of cellular stress when proteins are misfolded or are partially denatured.

Ubiquitin cycle inhibitors

Compounds that specifically block ubiquitin-cycle regulators such as USP9X.

Hasford score

Similar to the Sokal risk score, this is another prognostic score that can be used at diagnosis to classify patients as low risk, intermediate risk or high risk. This system was developed in 1998 and is based on the outcome of patients treated with interferon-α.

Carboxyfluorescein succinimidyl ester

(CFSE). A fluorescent dye commonly used in proliferation studies owing to halving of CFSE levels within daughter cells following successive divisions.

Long-term culture-initiating cells

An in vitro assay in which mononuclear cells or immunophenotypically selected haematopoietic cells (for example, CD34+ cells) are cultured on bone marrow stromal cells as feeders for up to 6 weeks, sometimes longer. After a defined interval of culture, the haematopoietic cells are harvested and assayed for clonogenic potential (colony growth) in semisolid medium.

P-loop

A conserved loop present in the ABL1 and BCR-ABL1 kinase domains that forms the roof of the active site and coordinates the γ-phosphate group of ATP.

Activation loop

A flexible loop that extends into the active kinase domain and functions as a binding platform for the peptide substrate to be phosphorylated.

Allogeneic stem cell transplant

The transfer of genetically similar but not identical cells from the bone marrow, peripheral blood or cord blood from one individual to another.

Sokal risk score

A prognostic score determined at diagnosis of chronic myeloid leukaemia to classify the patient as either low risk, intermediate risk or high risk. This is the most widely used scoring system, developed in 1984, when busulphan was the standard treatment. The score is based on spleen size, age, blast count and platelet count at diagnosis.

Synthetic lethality

In genetics, an interaction between two non-lethal mutations that, in combination, confer lethality. In chemical genetics, this term can refer to interaction between a drug and a mutation that confers greater drug sensitivity than with the wild type.

Autophagy

A cellular response in which the cell metabolizes its own contents and organelles to maintain energy production. Although such a process can eventually result in cell death, it can also be used to maintain cell survival under conditions of limiting nutrients.

Primary cytogenetic resistance

The inability to achieve a cytogenetic response on first exposure to TKIs.

Cyclosporine A

A calcineurin inhibitor immunosuppressant drug widely used to prevent T cell-mediated allograft rejection in solid organ transplantation and graft versus host disease in haematopoietic stem cell transplantation.

Graft versus leukaemia effect

A beneficial T cell-mediated immune response to host tumour cells by immune cells present in a donor's transplanted tissue.

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O'Hare, T., Zabriskie, M., Eiring, A. et al. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer 12, 513–526 (2012). https://doi.org/10.1038/nrc3317

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