title: BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD.
abstract: Recently, treatment with bromodomain and extraterminal protein antagonist (BA) such as JQ1 has been shown to inhibit growth and induce apoptosis of human acute myelogenous leukemia (AML) cells, including those expressing FLT3-ITD. Here, we demonstrate that cotreatment with JQ1 and the FLT3 tyrosine kinase inhibitor (TKI) ponatinib or AC220 synergistically induce apoptosis of cultured and primary CD34(+) human AML blast progenitor cells (BPC) expressing FLT3-ITD. Concomitantly, as compared with each agent alone, cotreatment with JQ1 and the FLT3-TKI caused greater attenuation of c-MYC, BCL2, and CDK4/6. Simultaneously, cotreatment with JQ1 and the FLT3-TKI increased the levels of p21, BIM, and cleaved PARP, as well as mediated marked attenuation of p-STAT5, p-AKT, and p-ERK1/2 levels in AML BPCs. Conversely, cotreatment with JQ1 and FLT3-TKI was significantly less active against CD34(+) normal bone marrow progenitor cells. Knockdown of BRD4 by short hairpin RNA also sensitized AML cells to FLT3-TKI. JQ1 treatment induced apoptosis of mouse Ba/F3 cells ectopically expressing FLT3-ITD with or without FLT3-TKI-resistant mutations F691L and D835V. Compared with the parental human AML FLT3-ITD-expressing MOLM13, MOLM13-TKIR cells resistant to AC220 were markedly more sensitive to JQ1-induced apoptosis. Furthermore, cotreatment with JQ1 and the pan-histone deacetylase inhibitor (HDI) panobinostat synergistically induced apoptosis of FLT3-TKI-resistant MOLM13-TKIR and MV4-11-TKIR cells. Collectively, these findings support the rationale for determining the in vivo activity of combined therapy with BA and FLT3-TKI against human AML cells expressing FLT3-ITD or with BA and HDI against AML cells resistant to FLT3-TKI.
authors: Baylor College of Medicine, Houston, Texas.
authors: Warren
authors: W
authors: Fiskus
authors: University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah.
authors: Sunil
authors: S
authors: Sharma
authors: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Jun
authors: J
authors: Qi
authors: Houston Methodist Research Institute, Houston, Texas.
authors: Bhavin
authors: B
authors: Shah
authors: Houston Methodist Research Institute, Houston, Texas.
authors: Santhana G T
authors: SG
authors: Devaraj
authors: Houston Methodist Research Institute, Houston, Texas.
authors: Christopher
authors: C
authors: Leveque
authors: Houston Methodist Research Institute, Houston, Texas.
authors: Bryce P
authors: BP
authors: Portier
authors: Houston Methodist Research Institute, Houston, Texas.
authors: Swaminathan
authors: S
authors: Iyer
authors: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: James E
authors: JE
authors: Bradner
authors: Houston Methodist Research Institute, Houston, Texas. knbhalla@tmhs.org.
authors: Kapil N
authors: KN
authors: Bhalla
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D011724:Pyridazines / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D007093:Imidazoles; D009687:Nuclear Proteins; D011724:Pyridazines; D014157:Transcription Factors; D014230:Triazoles; D040281:Vascular Endothelial Growth Factor Receptor-1; D051941:fms-Like Tyrosine Kinase 3; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C545373:ponatinib; C501162:FLT1 protein, human; C497970:FLT3 protein, human