title: 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.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Eiring
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Brent D G
authors.initials: BDG
authors.lastname: Page
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Ira L
authors.initials: IL
authors.lastname: Kraft
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Clinton C
authors.initials: CC
authors.lastname: Mason
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Vellore
authors.affiliation: York University Chemistry Department, Toronto, Ontario, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Resetca
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Zabriskie
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Tian Y
authors.initials: TY
authors.lastname: Zhang
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Jamshid S
authors.initials: JS
authors.lastname: Khorashad
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Engar
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Reynolds
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Senina
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Pomicter
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Carolynn C
authors.initials: CC
authors.lastname: Arpin
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Shazia
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Heaton
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Srinivas K
authors.initials: SK
authors.lastname: Tantravahi
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Todic
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: York University Chemistry Department, Toronto, Ontario, Canada.|Center for Research in Mass Spectrometry, Department of Chemistry, York University, Toronto, Ontario, Canada.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baron
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
authors.affiliation: 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.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D000636:Aminosalicylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D000069439:Dasatinib; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D017930:Genes, Reporter; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000636:Aminosalicylic Acids; D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; C000597560:BP-5-087; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D054852:Small Molecule Libraries; D013449:Sulfonamides; D013844:Thiazoles; D000068877:Imatinib Mesylate; D008156:Luciferases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib