The STAT5 Inhibitor Pimozide Displays Efficacy in Models of Acute Myelogenous Leukemia Driven by FLT3 Mutations

Genes and Cancer

Volumn 3, Issue 7-8, 2012, Pages 503-511

  Nelson, Erik A ^a   Walker, Sarah R ^a   Xiang, Michael ^a   Weisberg, Ellen ^a   Bar Natan, Michal ^a   Barrett, Rosemary ^a   Liu, Suiyang ^a   Kharbanda, Surender ^a   Christie, Amanda L ^b,c   Nicolais, Maria ^a   Griffin, James D ^a   Stone, Richard M ^a   Kung, Andrew L ^b,c   Frank, David A ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b DANA FARBER CANCER INSTITUTE   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

Author keywords

AML; FLT3; pimozide; STAT5

Indexed keywords

CD135 ANTIGEN; MIDOSTAURIN; PIMOZIDE; PROTEIN TYROSINE KINASE; STAT5 PROTEIN; SUNITINIB;

ACUTE GRANULOCYTIC LEUKEMIA; ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; ARTICLE; CELL VIABILITY; CONTROLLED STUDY; DRUG EFFICACY; DRUG MECHANISM; ENZYME ACTIVITY; FEMALE; GENE MUTATION; IMMUNOBLOTTING; IMMUNOPRECIPITATION; IN VITRO STUDY; INHIBITION KINETICS; LEUKEMIA CELL; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION;

EID: 84875545724     PISSN: 19476019     EISSN: 19476027     Source Type: Journal    
DOI: 10.1177/1947601912466555     Document Type: Article

References (32)

1. Haura EB,Turkson J,Jove R.Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer.Nat Clin Pract Oncol. 2006;2 (6): 315-24.
2. Sharma SV,Gajowniczek P,Way IP, et al.A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes.Cancer Cell. 2006;10 (5): 425-35.
3. Ito T,Tanaka H,Kimura A.Establishment and characterization of a novel imatinib-sensitive chronic myeloid leukemia cell line MYL, and an imatinib-resistant subline MYL-R showing overexpression of Lyn.Eur J Haematol. 2007;78 (5): 417-31.
4. Liu J,Joha S,Idziorek T, et al.BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism.Leukemia. 2008;22 (4): 791-9.
5. Zhou J,Bi C,Janakakumara JV, et al.Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML.Blood. 2009;113 (17): 4052-62.
6. Warsch W,Kollmann K,Eckelhart E, et al.High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia.Blood. 2011;117 (12): 3409-20.
7. Stone RM.Treatment of acute myeloid leukemia: state-of-the-art and future directions.Semin Hematol. 2002;39 (3): 4-10.
8. Cheng Y,Paz K.Tandutinib, an oral, small-molecule inhibitor of FLT3 for the treatment of AML and other cancer indications.IDrugs. 2008;11 (1): 46-56.
9. Fischer T,Stone RM,Deangelo DJ, et al.Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3.J Clin Oncol. 2010;28 (28): 4339-45.
10. Fathi AT,Chabner BA.FLT3 inhibition as therapy in acute myeloid leukemia: a record of trials and tribulations.Oncologist. 2011;16 (8): 1162-74.
11. Nakao M,Yokota S,Iwai T, et al.Internal tandem duplication of the flt3 gene found in acute myeloid leukemia.Leukemia. 1996;10 (12): 1911-8.
12. Mizuki M,Fenski R,Halfter H, et al.Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways.Blood. 2000;96 (12): 3907-14.
13. Weisberg E,Boulton C,Kelly LM, et al.Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412.Cancer Cell. 2002;1 (5): 433-43.
14. Nelson EA,Walker SR,Kepich A, et al.Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3.Blood. 2008;112 (13): 5095-102.
15. Nelson EA,Walker SR,Weisberg E, et al.The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors.Blood. 2011;117 (12): 3421-9.
16. Heidel FH,Mack TS,Razumovskaya E, et al.3,4-Diarylmaleimides-a novel class of kinase inhibitors-effectively induce apoptosis in FLT3-ITD-dependent cells.Ann Hematol. 2012;91 (3): 331-44.
17. O'Farrell AM,Abrams TJ,Yuen HA, et al.SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo.Blood. 2003;101 (9): 3597-605.
18. Weisberg E,Kung AL,Wright RD.Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells.Mol Cancer Ther. 2007;6 (7): 1951-61.
19. O'Farrell AM,Foran JM,Fiedler W, et al.An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients.Clin Cancer Res. 2003;9 (15): 5465-76.
20. Savage DG,Antman KH.Imatinib mesylate: a new oral targeted therapy.N Engl J Med. 2002;346 (9): 683-93.
21. Kantarjian H,Giles F,Wunderle L, et al.Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.N Engl J Med. 2006;354 (24): 2542-51.
22. Talpaz M,Shah NP,Kantarjian H, et al.Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.N Engl J Med. 2006;354 (24): 2531-41.
23. Gorre ME,Mohammed M,Ellwood K, et al.Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.Science. 2001;293 (5531): 876-80.
24. Chu SH,Small D.Mechanisms of resistance to flt3 inhibitors.Drug Resist Updat. 2009;12:8-16.
25. Heidel F,Solem FK,Breitenbuecher F, et al.Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain.Blood. 2006;107 (1): 283-300.
26. Libermann TA,Zerbini LF.Targeting transcription factors for cancer gene therapy.Curr Gene Ther. 2006;6 (1): 17-33.
27. Frank DA.Targeting transcription factors for cancer therapy.IDrugs. 2009;12 (1): 29-33.
28. Wang Z,Li G,Tse W,Bunting KD.Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement.Blood. 2009;113 (20): 4856-65.
29. Bar-Natan M,Nelson EA,Walker SR,Kuang Y,Distel RJ,Frank DA.Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells.Leukemia. 2012;26 (6): 1407-10.
30. Nelson EA,Sharma SV,Settleman J,Frank DA.A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation.Oncotarget. 2011;2 (6): 518-24.
31. Takakura A,Nelson EA,Haque N, et al.Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways.Hum Mol Genet. 2011;20 (21): 4143-54.
32. Armstrong SA,Kung AL,Mabon ME, et al.Inhibition of FLT3 in MLL: validation of a therapeutic target identified by gene expression based classification.Cancer Cell. 2003;3 (2): 173-83.