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Molecular Targets for Therapy

Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns

Leukemia volume 26, pages 1462–1470 (2012)Cite this article

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Abstract

Acquired resistance to selective FLT3 inhibitors is an emerging clinical problem in the treatment of FLT3-ITD+ acute myeloid leukaemia (AML). The paucity of valid pre-clinical models has restricted investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. We generated selective FLT3 inhibitor-resistant cells by treating the FLT3-ITD+ human AML cell line MOLM-13 in vitro with the FLT3-selective inhibitor MLN518, and validated the resistant phenotype in vivo and in vitro. The resistant cells, MOLM-13-RES, harboured a new D835Y tyrosine kinase domain (TKD) mutation on the FLT3-ITD+ allele. Acquired TKD mutations, including D835Y, have recently been identified in FLT3-ITD+ patients relapsing after treatment with the novel FLT3 inhibitor, AC220. Consistent with this clinical pattern of resistance, MOLM-13-RES cells displayed high relative resistance to AC220 and Sorafenib. Furthermore, treatment of MOLM-13-RES cells with AC220 lead to loss of the FLT3 wild-type allele and the duplication of the FLT3-ITD-D835Y allele. Our FLT3-Aurora kinase inhibitor, CCT137690, successfully inhibited growth of FLT3-ITD-D835Y cells in vitro and in vivo, suggesting that dual FLT3-Aurora inhibition may overcome selective FLT3 inhibitor resistance, in part due to inhibition of Aurora kinase, and may benefit patients with FLT3-mutated AML.

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Acknowledgements

We acknowledge NHS funding to the NIHR Biomedical Research Centre. This work, and all authors from Cancer Research UK Cancer Therapeutics Unit, are supported by core funding from Cancer Research UK (Grant numbers C309/A8274, C309/A11566). ASM is supported by Cancer Research UK (Grant number C1178/A10294) and in part by a New Investigator Scholarship awarded by the Haematology Society of Australia and New Zealand. ADJP is supported by Cancer Research UK (Programme Grant C1178/A10294). PW is a Cancer Research UK Life Fellow. SL is also supported by Breakthrough Breast Cancer.

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Author notes

  1. A Faisal and D Gonzalez de Castro: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cancer Therapeutics, Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Sutton, UK

    A S Moore, A Faisal, V Bavetsias, C Sun, B Atrash, M Valenti, A de Haven Brandon, S Avery, P Workman, J Blagg, F I Raynaud, S A Eccles & S Linardopoulos

  2. Division of Clinical Studies, The Institute of Cancer Research, Sutton, UK

    A S Moore, A D J Pearson & P Workman

  3. Paediatric Oncology, Royal Marsden NHS Foundation Trust, Sutton, UK

    A S Moore & A D J Pearson

  4. Division of Molecular Pathology, The Institute of Cancer Research, Sutton, UK

    D Gonzalez de Castro, D Mair, F Mirabella & J Swansbury

  5. Division of Breast Cancer Research, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK

    S Linardopoulos

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Correspondence to S Linardopoulos.

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All authors are employees of the Institute of Cancer Research, which has a commercial interest in drug development programmes (see www.icr.ac.uk). Please note that all authors who are, or have been, employed by the Institute of Cancer Research are subject to a ‘Rewards to Inventors Scheme’, which may reward contributors to a programme that is subsequently licensed.

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Moore, A., Faisal, A., de Castro, D. et al. Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns. Leukemia 26, 1462–1470 (2012). https://doi.org/10.1038/leu.2012.52

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