title: SCLLTargeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models.
abstract: Although over expression of chimeric FGFR1 kinase consistently leads to the development of AML in the rare Stem Cell Leukemia and Lymphoma syndrome, we now show that overexpression of FGFR1 is also seen in up to 20% of non-syndromic, de novo AML. To determine whether targeting FGFR1 in both of these AML subtypes can suppress leukemogenesis, we evaluated the effects of different FGFR1 inhibitors in a side-by-side comparison for their ability to affect in vitro proliferation in FGFR1 overexpressing murine and human cells lines. Three newly developed pan-FGFR inhibitors, AZD4547, BGJ398 and JNJ42756493, show a significantly improved efficacy over the more established FGFR inhibitors, PD173074 and TKI258. To examine whether targeting FGFR1 suppresses leukemogenesis in de novo AML in vivo, we created xenografts in immunocompromized mice from primary, de novo AML that showed > 3-fold increased expression of FGFR1. Using BGJ398, the most potent inhibitor identified in the in vitro studies, AML progression in these mice was significantly suppressed compared with vehicle treated animals and overall survival improved. Importantly, no difference in disease course or survival was seen in AML xenografts that did not show overexpression of FGFR1. These observations support the idea that FGFR1 is a driver oncogene in de novo, FGFR1-overexpressing AML and that molecularly targeted therapies using FGFR1 inhibitors may provide a valuable therapeutic regimen for all FGFR1-overexpressing AML.
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Bhole
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qin
authors.affiliation: Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Karp
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Sami
authors.initials: S
authors.lastname: Malek
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Cowell
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Ren
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D063646:Carcinogenesis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; C572463:AZD4547; D001549:Benzamides; D001562:Benzimidazoles; C115711:PD 173074; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D015363:Quinolones; C568950:infigratinib; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: AML; FGFR1; NSG-SGM3 mice; therapeutics; xenograft