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Mechanisms of resistance

Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo

Leukemia volume 35, pages 2017–2029 (2021)Cite this article

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Abstract

An important limitation of FLT3 tyrosine kinase inhibitors (TKIs) in FLT3-ITD positive AML is the development of resistance. To better understand resistance to FLT3 inhibition, we examined FLT3-ITD positive cell lines which had acquired resistance to midostaurin or sorafenib. In 6 out of 23 TKI resistant cell lines we were able to detect a JAK1 V658F mutation, a mutation that led to reactivation of the CSF2RB–STAT5 pathway. Knockdown of JAK1, or treatment with a JAK inhibitor, resensitized cells to FLT3 inhibition. Out of 136 patients with FLT3-ITD mutated AML and exposed to FLT3 inhibitor, we found seven different JAK family mutations in six of the cases (4.4%), including five bona fide, activating mutations. Except for one patient, the JAK mutations occurred de novo (n = 4) or displayed increasing variant allele frequency after exposure to FLT3 TKI (n = 1). In vitro each of the five activating variants were found to induce resistance to FLT3-ITD inhibition, which was then overcome by dual FLT3/JAK inhibition. In conclusion, our data characterize a novel mechanism of resistance to FLT3-ITD inhibition and may offer a potential therapy, using dual JAK and FLT3 inhibition.

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Fig. 1: FLT3-ITD independent STAT5 and CSF2RB phosphorylation/activation confers resistance to FLT3 TKIs in vitro.
Fig. 2: Mutant JAK1 mediates resistance to FLT3 inhibitors that can be overcome by dual inhibition of FLT3 and JAK1/2.
Fig. 3: Dual FLT3 and JAK inhibition overcomes FLT3-TKI resistance mediated by JAK mutations found in FLT3-TKI treated patients.
Fig. 4: Dual FLT3 and JAK inhibition blocks downstream signaling of cells simulating the resistance mechanisms found in FLT3-TKI treated patients.

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Acknowledgements

This work was supported by a grant to NvB from the Deutsche Forschungsgemeinschaft No. BU 2508/4–1, by a grant to JD and NvB from the Bundesministerium für Bildung und Forschung (NGFNplus) and by a grant to JD and NvB from the José Carreras Stiftung No. 106682. Proofreading was performed by Dr. Marie Follo

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Authors and Affiliations

  1. Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Christoph Rummelt, Anne Charlet, Cornelia Endres, Justus Duyster & Nikolas von Bubnoff

  2. Department of Hematology and Oncology, Medical Center, University of Schleswig-Holstein, Lübeck, Germany

    Sivahari P. Gorantla & Nikolas von Bubnoff

  3. MLL Munich Leukemia Laboratory, Munich, Germany

    Manja Meggendorfer & Torsten Haferlach

  4. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Cornelia Endres, Justus Duyster & Nikolas von Bubnoff

  5. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    Konstanze Döhner

  6. Innere Medizin 2, Universitätsklinikum Jena, Jena, Germany

    Florian H. Heidel

  7. Innere Medizin C, Universitätsmedizin Greifswald, Greifswald, Germany

    Florian H. Heidel

  8. Department of Hematology and Oncology, Medical Center, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

    Thomas Fischer

  9. German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany

    Justus Duyster & Nikolas von Bubnoff

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Contributions

NvB, JD, and CR designed experiments and wrote the manuscript. CR, SPG, AC, and CE performed experiments. MM, KD, FH, TF, and TH provided patient samples and patient data. TF provided constructs.

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Correspondence to Nikolas von Bubnoff.

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NvB received honoraria from Amgen, Astra Zeneca, BMS and Novartis, and research funding from Novartis. JD received honoraria from Novartis. The authors have no additional financial interests.

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Rummelt, C., Gorantla, S.P., Meggendorfer, M. et al. Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo. Leukemia 35, 2017–2029 (2021). https://doi.org/10.1038/s41375-020-01077-1

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