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Chronic Myeloproliferative Neoplasias

Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia

Leukemia volume 29, pages 586–597 (2015)Cite this article

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An Erratum to this article was published on 03 May 2017

Abstract

Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen–deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from chronic myeloid leukemia (CML) patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 μM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells. Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation.

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Acknowledgements

We acknowledge Johanna Estrada, Kevin Gantz, Hannah Redwine, Hillary Finch and Anthony Iovino for technical assistance, and Kimberly Snow and Candice Ott for clerical assistance. We thank Dr Rob C Laister and the Minden group for providing full-length purified STAT3 protein and a STAT3 expression construct. We also thank Dr Il-Hoan Oh, Catholic University of Korea, for providing a dominant-negative STAT3 construct. We acknowledge support of funds in conjunction with grant P30 CA042014 awarded to the Huntsman Cancer Institute, and 5P30CA042014-24 awarded to The University of Utah Flow Cytometry Facility. MWD was supported by grants from the National Institutes of Health (NIH), including HL082978-01, CA046939-23 and R01CA178397, was a Scholar in Clinical Research of the Leukemia & Lymphoma Society (LLS; 7036-01), and is funded by LLS grant SCOR7005-11. AME was supported by a NIH T32 training grant (CA093247), followed by an LLS Career Development Award (5090-12), and is currently funded through a Scholar Award from the American Society of Hematology. AME also acknowledges support from the NIH Loan Repayment Program. This research was supported in part by the LLS Screen-to-Lead Program awarded to MWD, TO and PTG (SLP-8002-14). TO is supported by NIH grant R01CA178397. RB acknowledges a petascale computing Research Award at the Extreme Science and Engineering Discovery Environment (XSEDE) supercomputers (TG-CHE120086). XSEDE is supported by National Science Foundation grant OCI-1053575. RB acknowledges startup funds from the Department of Medicinal Chemistry, and technical support and computing allocations at the Center for High Performance Computing, The University of Utah. RM was supported by grant SFBF47 from the Austrian Science Fund (FWF). PTG and BDGP are supported by the National Sciences and Engineering Research Council. PTG is also supported by the Canadian Breast Cancer Research Foundation. DJW is supported by a Discovery Grant (257588) and by an Ontario Ministry of Research and Innovation Early Researcher Award.

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Author notes

  1. A M Eiring, B D G Page, I L Kraft, T O'Hare, P T Gunning and M W Deininger: These authors contributed equally to this work.

  2. These authors contributed equally to this work.

Authors and Affiliations

  1. Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA

    A M Eiring, I L Kraft, C C Mason, M S Zabriskie, T Y Zhang, J S Khorashad, A J Engar, K R Reynolds, D J Anderson, A Senina, A D Pomicter, W L Heaton, S K Tantravahi, T O'Hare & M W Deininger

  2. Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada

    B D G Page, C C Arpin, A Todic, R Colaguori & P T Gunning

  3. Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA

    N A Vellore, S Ahmad & R Baron

  4. York University Chemistry Department, Toronto, Ontario, Canada

    D Resetca & D J Wilson

  5. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

    R Moriggl

  6. Department of Chemistry, Center for Research in Mass Spectrometry, York University, Toronto, Ontario, Canada,

    D J Wilson

  7. Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, USA

    T O'Hare & M W Deininger

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  1. A M Eiring
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Correspondence to M W Deininger.

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Competing interests

MWD is a consultant for BMS, Novartis, ARIAD, Pfizer and Incyte. His laboratory receives research funding from BMS and Novartis.

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Eiring, A., Page, B., Kraft, I. et al. Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia. Leukemia 29, 586–597 (2015). https://doi.org/10.1038/leu.2014.245

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