Targeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models

Qing Wu, Aaron Bhole, Haiyan Qin, Judith Karp, Sami Malek, John Kenneth Cowell, Mingqiang Ren

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)49733-49742
Number of pages10
JournalOncotarget
Volume7
Issue number31
DOIs
StatePublished - Jan 1 2016

Fingerprint

Heterografts
Survival
Oncogenes
Lymphoma
Leukemia
Phosphotransferases
Stem Cells
Cell Line
Therapeutics
3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea
In Vitro Techniques
AZD4547
PD 173074
4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one

Keywords

  • AML
  • FGFR1
  • NSG-SGM3 mice
  • Therapeutics
  • Xenograft

ASJC Scopus subject areas

  • Oncology

Cite this

Targeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models. / Wu, Qing; Bhole, Aaron; Qin, Haiyan; Karp, Judith; Malek, Sami; Cowell, John Kenneth; Ren, Mingqiang.

In: Oncotarget, Vol. 7, No. 31, 01.01.2016, p. 49733-49742.

Research output: Contribution to journalArticle

Wu, Qing ; Bhole, Aaron ; Qin, Haiyan ; Karp, Judith ; Malek, Sami ; Cowell, John Kenneth ; Ren, Mingqiang. / Targeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models. In: Oncotarget. 2016 ; Vol. 7, No. 31. pp. 49733-49742.
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