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

Autor: Eiring AM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Page BDG; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada., Kraft IL; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Mason CC; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Vellore NA; Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA., Resetca D; York University Chemistry Department, Toronto, Ontario, Canada., Zabriskie MS; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Zhang TY; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Khorashad JS; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Engar AJ; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Reynolds KR; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Anderson DJ; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Senina A; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Pomicter AD; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Arpin CC; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada., Ahmad S; Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA., Heaton WL; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Tantravahi SK; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Todic A; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada., Moriggl R; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria., Wilson DJ; York University Chemistry Department, Toronto, Ontario, Canada.; Center for Research in Mass Spectrometry, Department of Chemistry, York University, Toronto, Ontario, Canada., Baron R; Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA., O'Hare T; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah, USA., Gunning PT; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada., Deininger MW; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah, USA.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2015 Mar; Vol. 29 (3), pp. 586-597. Date of Electronic Publication: 2014 Aug 19.
DOI: 10.1038/leu.2014.245
Abstrakt: 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.
Databáze: MEDLINE