Data from Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma

• DOI: 10.1158/0008-5472.c.7104593
• Publication Date: 2024-03-04T22:25:30Z
• Authors: Sana Hosni; Viola Kilian; Niklas Klümper; Daniela Gabbia; Katharina Sieckmann; Dillon Corvino; Anja Winkler; Miriam Saponaro; Karin Wörsdörfer; Doris Schmidt; Oliver Hahn; Ilaria Zanotto; Marina Bertlich; Marieta Toma; Tobias Bald; Markus Eckstein; Michael Hölzel; Matthias Geyer; Manuel Ritter; Dagmar Wachten; Sara De Martin; Abdullah Alajati
• Keywords: Urothelial cancer

<div>Abstract<p>Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic urothelial cancer (mUC), and blocking FGF/FGFR signaling axis is used as a targeted therapeutic strategy for treating patients. Erdafitinib pan-FGFR inhibitor, which has recently been approved by FDA mUC with FGFR2/3 alterations. Although patients show initial response to erdafitinib, acquired resistance rapidly develops. Here, we found that adipocyte precursors promoted erdafitinib FGFR-dependent bladder lung paracrine manner. Moreover, neuregulin 1 (NRG1) secreted from was mediator activating human epidermal 3 (ERBB3; also known HER3) signaling, knockdown NRG1 abrogated conferred resistance. expression significantly downregulated terminally differentiated adipocytes compared their progenitors. Pharmacologic inhibition NRG1/HER3 using pertuzumab reversed tumor cells <i>in vitro</i> prolonged survival mice bearing xenografts vivo</i>. Remarkably, data single-cell RNA sequencing revealed enriched platelet-derived receptor-A (PDGFRA) expressing inflammatory cancer-associated fibroblasts, expressed on precursors. Together, this work reveals mechanism anti-FGFR cancer, potentially other cancers, amenable available therapies.</p>Significance:<p>Acquired FGFR can be activation mediated overcome combination treatment.</p><p><i><a href="https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-23-3904" target="_blank">See related commentary Kolonin Anastassiou, p. 648</a></i></p></div>