Sana Hosni1, Viola Kilian1, Niklas Klümper1,2, Daniela Gabbia3, Katharina Sieckmann4, Dillon Corvino2, Anja Winkler1, Miriam Saponaro1, Karin Wörsdörfer1, Doris Schmidt1, Oliver Hahn5,6, Ilaria Zanotto3, Marina Bertlich1, Marieta Toma7, Tobias Bald2, Markus Eckstein8, Michael Hölzel2, Matthias Geyer9, Manuel Ritter1, Dagmar Wachten4, Sara De Martin3, Abdullah Alajati1
1 Department of Urology and Pediatric Urology, University Hospital Bonn (UKB), Bonn, Germany
2 Institute of Experimental Oncology, University Hospital Bonn (UKB), Bonn, Germany
3 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
4 Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany
5 Clinic of Urology, University Hospital Göttingen, Göttingen, Germany
6 Clinic of Urology, University Hospital Würzburg, Würzburg, Germany
7 Institute of Pathology, University Hospital Bonn (UKB), Bonn, Germany
8 Institute of Pathology, University Hospital Erlangen, Erlangen-Nuernberg (FAU), Erlangen, Germany
9 Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany
* Authors contributed equally
Correspondence: Abdullah Alajati
Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic urothelial cancer (mUC), and blocking the FGF/FGFR signaling axis is used as a targeted therapeutic strategy for treating patients. Erdafitinib is a pan-FGFR inhibitor, which has recently been approved by the FDA for mUC 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 in a paracrine manner.
Moreover, neuregulin 1 (NRG1) secreted from adipocyte precursors was a mediator of erdafitinib resistance by activating human epidermal growth factor receptor 3 (ERBB3; also known as HER3) signaling, and knockdown of NRG1 in adipocyte precursors abrogated the conferred paracrine resistance. NRG1 expression was significantly downregulated in terminally differentiated adipocytes compared with their progenitors.
Pharmacologic inhibition of the NRG1/HER3 axis using pertuzumab reversed erdafitinib resistance in tumor cells in vitro and prolonged survival of mice bearing 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.
Together, this work reveals a paracrine mechanism of anti-FGFR resistance in bladder cancer, and potentially other cancers, that is amenable to inhibition using available targeted therapies.
Significance: Acquired resistance to FGFR inhibition can be rapidly promoted by paracrine activation of the NRG1/HER3 axis mediated by adipocyte precursors and can be overcome by the combination of pertuzumab and erdafitinib treatment.
The processed single-cell RNA-seq objects (Seurat / CellView) are archived on Zenodo (open access): 10.5281/zenodo.21401004. Raw sequencing reads are deposited on GEO — see the published paper's data-availability statement for the accession.
This code and analysis were authored by Dillon Corvino — github.com/Eomesodermin · dilloncorvino.com.