title: The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors.
abstract: The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, although CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we used a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, although it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes and induces cell cycle arrest and apoptosis in CML cell lines. Pimozide also selectively inhibits colony formation of CD34(+) bone marrow cells from CML patients. Importantly, pimozide induces similar effects in the presence of the T315I BCR/ABL mutation that renders the kinase resistant to presently available inhibitors. Simultaneously inhibiting STAT5 with pimozide and the kinase inhibitors imatinib or nilotinib shows enhanced effects in inhibiting STAT5 phosphorylation and in inducing apoptosis. Thus, targeting STAT5 may be an effective strategy for the treatment of CML and other myeloproliferative diseases.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Nelson
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walker
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: Michal
authors.initials: M
authors.lastname: Bar-Natan
authors.forename: Rosemary
authors.initials: R
authors.lastname: Barrett
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Gashin
authors.forename: Shariya
authors.initials: S
authors.lastname: Terrell
authors.forename: Josephine L
authors.initials: JL
authors.lastname: Klitgaard
authors.forename: Loredana
authors.initials: L
authors.lastname: Santo
authors.forename: Martha R
authors.initials: MR
authors.lastname: Addorio
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D010868:Pimozide / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors*; D017211:Treatment Failure; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D010868:Pimozide; D016044:Fusion Proteins, bcr-abl