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

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.

• Authors: Anna M Eiring, Brent D G Page, Ira L Kraft, Clinton C Mason, Nadeem A Vellore, Diana Resetca, Matthew S Zabriskie, Tian Y Zhang, Jamshid S Khorashad, Alexander J Engar, Kimberly R Reynolds, David J Anderson, Anna Senina, Anthony D Pomicter, Carolynn C Arpin, Shazia Ahmad, William L Heaton, Srinivas K Tantravahi, Aleksandra Todic, Richard Moriggl, Derek J Wilson, Riccardo Baron, Thomas O'Hare, Patrick T Gunning, Michael W Deininger
• Journal: Leukemia (Leukemia) Vol. 29 Issue 3 Pg. 586-597 (Mar 2015) ISSN: 1476-5551 [Electronic] England
• PMID: 25134459 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 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
• nilotinib
• Dasatinib

Topics

• Aminosalicylic Acids (chemical synthesis, chemistry, 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, genetics, metabolism)
• Gene Expression Regulation, Leukemic
• Genes, Reporter
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism, pathology)
• Leukocytes, Mononuclear (drug effects, metabolism, pathology)
• Luciferases (genetics, metabolism)
• Molecular Docking Simulation
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Phosphorylation
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Structure, Tertiary
• Pyrimidines (pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors, chemistry, genetics, metabolism)
• Signal Transduction
• Small Molecule Libraries (chemical synthesis, chemistry, pharmacology)
• Sulfonamides (chemical synthesis, chemistry, pharmacology)
• Thiazoles (pharmacology)