An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers

EMBO Molecular Medicine
Mélanie MaheIsabelle Bernard-Pierrot

Abstract

FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3 Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti-FGFR treatment in a PDX model bearing an FGFR3 mutation. These findings open up new possibilities for the treatment of bladder tumors displaying aberrant FGFR3 activation.

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Citations

Aug 2, 2019·International Journal of Urology : Official Journal of the Japanese Urological Association·Takahiro YoshidaDavid J McConkey
Jul 13, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Chengle ZhuangYaoting Gui
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Jan 6, 2021·Genome Biology·Xiaoping SuGabriel G Malouf
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May 8, 2021·Hematology/oncology Clinics of North America·Shaoming ZhuChong-Xian Pan
Sep 4, 2020·Signal Transduction and Targeted Therapy·Yangli XieLin Chen

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Datasets Mentioned

BETA
GSE84733

Methods Mentioned

BETA
xenograft
transfection
immunoprecipitation
PCR
xenografts
chip
protein array
protein assay

Clinical Trials Mentioned

NCT02159066
NCT01928459

Software Mentioned

ArrayExpress
Ingenuity Pathway Analysis
Ingenuity Pathway Analysis ( IPA )

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