2. Academic Validation
  3. Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia

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

  • Leukemia. 2015 Mar;29(3):586-597. doi: 10.1038/leu.2014.245.
Anna M Eiring # 1,  Brent D G Page # 2,  Ira L Kraft # 1,  Clinton C Mason 1,  Nadeem A Vellore 3,  Diana Resetca 4,  Matthew S Zabriskie 1,  Tian Y Zhang 1,  Jamshid S Khorashad 1,  Alexander J Engar 1,  Kimberly R Reynolds 1,  David J Anderson 1,  Anna Senina 1,  Anthony D Pomicter 1,  Carolynn C Arpin 2,  Shazia Ahmad 3,  William L Heaton 1,  Srinivas K Tantravahi 1,  Aleksandra Todic 2,  Richard Moriggl 5,  Derek J Wilson 4 6,  Riccardo Baron 3,  Thomas O'Hare # 1 7,  Patrick T Gunning # 2,  Michael W Deininger # 1 7
Affiliations

Affiliations

  • 1 Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
  • 2 Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada.
  • 3 Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.
  • 4 York University Chemistry Department, Toronto, Ontario, Canada.
  • 5 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
  • 6 Center for Research in Mass Spectrometry, Department of Chemistry, York University, Toronto, Ontario, Canada.
  • 7 Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah, USA.
  • # Contributed equally.
PMID: 25134459 DOI: 10.1038/leu.2014.245
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-117770
    STAT3抑制剂
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