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
  • 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.

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