gms | German Medical Science

69. Kongress der Nordrhein-Westfälischen Gesellschaft für Urologie

Nordrhein-Westfälische Gesellschaft für Urologie e. V.

11.04. - 12.04.2024, Essen

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Adipocyte precursor-derived NRG1 promotes resistance to FGFR inhibition in urothelial carcinoma

Meeting Abstract

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  • S. Hosni - Universitätsklinikum Bonn, Klinik und Poliklinik für Urologie und Kinderurologie, Bonn, Deutschland
  • V. Kilian - Universitätsklinikum Bonn, Klinik und Poliklinik für Urologie und Kinderurologie, Bonn, Deutschland
  • Niklas Klümper - Universitätsklinikum Bonn, Klinik und Poliklinik für Urologie und Kinderurologie, Bonn, Deutschland
  • M. Saponaro - Universitätsklinikum Bonn, Klinik und Poliklinik für Urologie und Kinderurologie, Bonn, Deutschland
  • M. Eckstein - Institute of Pathology, University Hospital Erlangen, Erlangen, Germany
  • Manuel Ritter - Universitätsklinikum Bonn, Klinik und Poliklinik für Urologie und Kinderurologie, Bonn, Deutschland
  • presenting/speaker Abdullah Alajati - Universitätsklinikum Bonn, Klinik und Poliklinik für Urologie und Kinderurologie, Bonn, Deutschland

Nordrhein-Westfälische Gesellschaft für Urologie. 69. Kongress der Nordrhein-Westfälischen Gesellschaft für Urologie. Essen, 11.-12.04.2024. Düsseldorf: German Medical Science GMS Publishing House; 2024. DocV 2.8

doi: 10.3205/24nrwgu15, urn:nbn:de:0183-24nrwgu154

Veröffentlicht: 26. März 2024

© 2024 Hosni et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.

Gliederung

Text

The prognosis of patients with metastatic urothelial cancer (mUC) remains poor and improving treatment continues to be a major medical need. Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in mUC and blocking the FGF/FGFR signaling axis is used as a targeted therapeutic strategy. Erdafitinib is a pan-FGFR inhibitor that has been recently approved by the Food and Drug Administration for mUC patients with FGFR2/3 alterations. Although mUC patients show initial response to erdafitinib, acquired resistance rapidly develops. Here we found that adipocyte precursors promoted resistance to erdafitinib in FGFR-dependent bladder and lung cancer cell lines in a paracrine manner. Moreover, we identified Neuregulin 1 (NRG1) secreted from adipocyte precursors as a mediator of erdafitinib resistance by activating Human Epidermal Growth factor receptor 3 (HER3) signaling. Knockdown of NRG1 in adipocyte precursors abrogated the paracrine resistance conferred by the parental cells. Nrg1 mRNA expression was significantly downregulated in terminally differentiated adipocytes compared to their progenitors. Furthermore, pharmacological inhibition of the NRG1/HER3 axis using pertuzumab reversed erdafitinib resistance in tumor cells in vitro, and prolonged survival of bladder cancer xenografts in vivo. Remarkably, data from single-cell RNA-sequencing revealed that NRG1 was enriched in platelet-derived growth factor receptor-A (PDGFRA) expressing inflammatory cancer-associated fibroblasts, which is also expressed on adipocyte precursors. Our work reveals a novel paracrine mechanism of anti-FGFR resistance in bladder cancer, and potentially to other cancers, amenable to clinical testing using available targeted therapies.