Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Pichler, R; van, Creij, NCH; Mertens, LS; Del, Giudice, F; Koll, F; Soria, F; Subiela, JD; Plage, H; Tymoszuk, P; Mayr, R; Klinglmair, G; Seeber, A; Pichler, M; Günther, M; Ormanns, S; Compérat, E; Li, R; Moschini, M; Pradére, B, , European, Association, of, Urology-Young, Academic, Urologists, Urothelial, Carcinoma, Working, Group.
FGFR1/3 Signaling as an Achilles' Heel of Phenotypic Diversity in Urothelial Carcinoma.
Eur Urol Oncol. 2025;
Doi: 10.1016/j.euo.2025.07.005
PubMed
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- Co-Autor*innen der Med Uni Graz
- Koll Florestan Johannes
- Pichler Martin
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- Abstract:
- FGFR inhibitors are a new therapeutic option for urothelial carcinoma (UC) with FGFR2/3 alterations. In this study, we analyzed genetic alterations, co-regulation, and differential expression for 45 genes encoding FGF, FGFR, or FGF-binding proteins (FGFBPs) in five published UC cohorts (n = 3939 MIBC) and 39 UC cell lines (DepMap portal). Network analyses identified FGFR1/3 genes as critical oncogenic hubs, co-regulated with their ligands and co-receptors, and abundantly expressed at protein level in the HPA immunohistochemistry data set. Machine learning with 38 FGFR-, FGF-, and FGFBP-coding transcripts reproduced consensus molecular subtypes with high accuracy of 0.72-0.84 (Cohen's κ 0.59-0.77). FGFR3 mutations in the transmembrane/hinge region, which were enriched in luminal papillary tumors, trigger ligand-independent signaling. Conversely, overexpression of FGFR1 and its ligands and accessory protein transcripts indicates ligand-dependent FGFR1 signaling in stroma-rich and basal/squamous subtypes. The sensitivity of most DepMap UC cell lines to pan-FGFR inhibitors in the GDSC and PRISM drug screens was independent of FGFR3 alterations. In vitro, erdafitinib reduced proliferation in FGFR wild-type UC cell lines in a similar manner to FGFR3-mutated cell lines. Our findings highlight FGFR1 and FGFR3 as pivotal signaling pathways with distinct, molecular subtype-specific activation mechanisms. The results suggest that FGFR inhibitors may have therapeutic applications beyond UC tumors with FGFR2/3 alterations.