EYES2023 ESE Young Endocrinologists and Scientists (EYES) 2023 Oral communication 3: Adrenal Tumors and Neuroendocrine Tumors (7 abstracts)
FGF/FGFR signaling in adrenocortical tumorigenesis: Novel potential therapeutic targets in adrenocortical carcinoma
Lena Kappenstein 1 , Alexander Paul 1 , Barbara Altieri 1 , Iuliu Sbiera 1 , Sigala Sandra 2 , Berruti Alfredo 3 , Martin Fassnacht 4 , Silviu Sbiera 1 & Mariangela Tamburello 5
1Division of Endocrinology, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany; 2Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; 3Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and Asst Spedali Civili DI Brescia, Brescia, Italy; 4Division of Endocrinology, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Comprehenssive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany, Germany; 5Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Division of Endocrinology, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany, Italy.
Background: Adrenocortical carcinoma (ACC) is one of the most aggressive endocrine malignancies. The Fibroblast Growth Factor/Fibroblast Growth Factor Receptor (FGF/FGFR) pathway plays a role in both embryogenesis and tumorigenesis of adrenal gland. Our group demonstrated that FGFR1-4 were upregulated in ACCs and that their high expression was significantly associated with worse prognosis, suggesting that they are potentially interesting therapeutic targets.
Objectives: To evaluate the effect of FGFR-inhibitors (erdafitinib, rogaratinib and fisogatinib) on different ACC cell lines as single treatment and in combination with most used chemotherapeutic drugs (gemcitabine, etoposide or streptozotocin) to scrutinize possible new treatment options for ACC patients.
Methods: FGFRs expression was evaluated by qRT-PCR on six ACC cell lines. For IC50 assessment, cells were treated with increasing concentrations of each drug for four days and cell viability was evaluated using CellTiter-Glo-Assay. Combination experiments were performed on NCI-H295R and TVBF-7 according to the Chou-Talalay method.
Results: All cell lines exhibited weak levels of FGFR1-IIIb and high levels of FGFR1-IIIc isoform. TVBF-7 showed unique expression pattern with highest levels of FGFR2 IIIb, FGFR2 IIIc and FGFR4. In MUC-1, JIL-2266 and CU-ACC2 cells, lower and variable levels of both FGFR2 isoforms and FGFR4 were found. Erdafitinib and rogaratinib, exerted a concentration-dependent effect in all cell lines with TVBF-7 cells being most sensitive (erdafitinib-IC50=0.1 μM, rogaratinib-IC50=0.78 μM). Conversely, the FGFR4-inhibitor fisogatinib did not affect cell viability up to 50 μM except on NCI-H295R and JIL-2266. Combination treatment of gemcitabine or streptozotocin with erdafitinib or rogaratinib significantly reduced cell viability, compared to single treatments (P<0.05).
Conclusions: Our preliminary results showed that TVBF-7 cells, with highest expression of FGFRs, were more sensitive to the pan-FGFR-inhibitors and that in all cell lines their effect is enhanced by gemcitabine or streptozotocin supporting the role of FGFR targeting in this rare disease with otherwise dismal outcome.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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