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. Epub 2014 Aug 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminosalicylic Acids / chemical synthesis
  • Aminosalicylic Acids / chemistry
  • Aminosalicylic Acids / pharmacology*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Dasatinib
  • Drug Discovery
  • Drug Resistance, Neoplasm / drug effects
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / genetics*
  • Fusion Proteins, bcr-abl / metabolism
  • Gene Expression Regulation, Leukemic*
  • Genes, Reporter
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • Luciferases / genetics
  • Luciferases / metabolism
  • Molecular Docking Simulation
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Phosphorylation
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Pyrimidines / pharmacology
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / chemistry
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Thiazoles / pharmacology

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Aminosalicylic Acids
  • Antineoplastic Agents
  • BCR-ABL1 fusion protein, human
  • BP-5-087
  • Benzamides
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Small Molecule Libraries
  • Sulfonamides
  • Thiazoles
  • Imatinib Mesylate
  • Luciferases
  • Fusion Proteins, bcr-abl
  • Dasatinib