Artikel
Pre-adipocyte-driven NRG1 promotes resistance to FGFR3 inhibition in urothelial carcinoma
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Autoren
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Sana Hosni
- Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany
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Viola Kilian
- Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany
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Niklas Klümper
- Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany
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Daniela Gabbia
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
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Anja Winkler
- Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany
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Miriam Saponaro
- Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany
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Doris Schmidt
- Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany
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Damian J. Ralser
- Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany
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Dillon Corvino
- Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany
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Marieta Toma
- Institute of Pathology, University Medical Center Bonn (UKB), Bonn, Germany
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Glen Kristiansen
- Institute of Pathology, University Medical Center Bonn (UKB), Bonn, Germany
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Tobias Bald
- Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany
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Markus Eckstein
- Institute of Pathology, University Hospital Erlangen, Erlangen-Nuremberg (FAU), Erlangen, Germany
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Dagmar Wachten
- Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany
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Manuel Ritter
- Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany
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Michael Hölzel
- Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany
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Matthias Geyer
- Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany
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Sara de Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
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Abdullah Alajati
- Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany
| Veröffentlicht: | 28. März 2023 |
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Gliederung
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Introduction: The prognosis of patients with metastatic urothelial cancer (mUC) remains poor and improving treatment continues to be a major medical need. The aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in UC, and blocking the FGF/FGFR signaling axis is a targeted therapeutic strategy in UC. Erdafitinib is a pan-FGFR1-4 inhibitor that has been recently approved by the Food and Drug Administration (FDA) for mUC patients with FGFR2/3 alterations. Although UC patients show initial response to Erdafitinib, acquired resistance rapidly develops.
Methods: Conditioned media (CM) of 3T3-L1 pre-adipocytic cells and human adipocyte-derived stem cells was tested for its ability to modulate the response to Erdafitinib in Erdafitinib-sensitive cells; RT4 and RT112. Proliferation was analyzed using crystal violet staining. Western blot analyses was done for (p)ERK1/2 and (p)AKT to assess an on-target response of Erdafitinib and investigate the paracrine effect of 3T3-L1 CM on signaling in cancer cells, respectively. 3T3-L1 cells were differentiated to adipocytes, and CM of these adipocytes was also tested on RT4 cells treated with Erdafitinib. Publicly available single cells RNA sequencing data was analyzed for PDGFRA and NRG1 using Seurat version 4.1.1. RT4 cells stably expressing NRG1 were injected in SCID mice and xenografts were analyzed for Ki67 expression by immunohistochemistry.
Results: We identified NRG1 secreted from pre-adipocytes as the mediator of Erdafitinib resistance in bladder cancer cells. Interestingly, the resistance phenotype was restricted to pre-adipocytes, since terminally differentiated adipocytes failed to promote anti-FGFRs resistance. Pharmacological blockade of the NRG1/HER3 axis using Pertuzumab re-sensitized bladder cancer cells to Erdafitinib in vitro and in vivo. FGFR-dependent lung cancer cells, LK2, recapitulated the resistance phenotype conferred by preadipocytes’ conditioned media, and the resensitization to Erdafitinib using Pertuzumab.
Conclusion: This work reveals a novel paracrine mechanism of anti-FGFR resistance in bladder cancer mediated by preadipocyte-derived NRG1. Combination therapy using clinically available HER2/HER3 axis inhibitory antibodies such as Pertuzumab with Erdafitinib is proposed to overcome acquired resistance against Erdafitinib.
