Abstract 5185: Analysis of the role of FGFR signaling in liposarcomas: Dual targeting of FGFR and MDM2 is synergistic

Abstract

Abstract Clinical trials have shown the benefits of FGFR inhibitors; notably, the oral pan-FGFR inhibitor JNJ-42756493 (erdafitinib) has recently been the first FGFR kinase inhibitor to receive US FDA approval for the treatment of patients with advanced or metastatic urothelial carcinoma. Our objectives were to show that the FGFR pathway is involved in liposarcoma (LPS) pathogenesis and to investigate the therapeutic potential of erdafitinib for LPS patients. LPS is the most common soft tissue sarcoma. Among LPS, well-differentiated/dedifferentiated LPS (WD/DDLPS) are the most frequent types. DDLPS have metastatic potential and a poor prognosis with a five-year mortality rate of 30%. Standard chemotherapies are inefficient and new therapeutic options are needed. FRS2, a crucial adaptor protein of the FGFR signaling pathway is overexpressed in most WD/DDLPS suggesting involvement of the FGFR pathway in LPS tumorigenesis. Immunohistochemistry was used to perform an exhaustive analysis of the expression pattern of FGFR1-4 in WD/DDLPS both in a large collection of 421 primary tumors and in our in-house panel of validated human WDLPS and DDLPS cell lines. Cells were exposed to erdafitinib - as a single agent or in combination - and apoptosis and signalling pathway perturbations were monitored by flow cytometry and western blotting. Xenograft mouse models were used to confirm our in vitro results in the in vivo setting. We have detected a high expression of FGFR1 and/or FGFR4 in a significant percentage of WDLPS and DDLPS and demonstrated that this expression is correlated with poor prognosis. Exposure of LPS cells to erdafitinib induced a decrease in cell viability, cell cycle arrest in G1 and apoptosis. Erdafitinib treatment had a strong inhibitory effect on the ERK1/2 pathway whereas the PI3K/AKT pathway was less affected. The PI3K/mTOR antagonist BEZ235 was not synergistic with erdafitinib in DDLPS cells. MDM2 overexpression being the hallmark of WD/DDLPS, we investigated the effects of the MDM2-TP53 interaction inhibitor RG7388 (idasanutlin) in combination with erdafitinib. Interestingly, we found that the combination of RG7388 and erdafitinib exerts a highly synergistic effect on both viability and apoptosis in all our WDLPS and DDLPS cell lines. We are currently investigating the mechanics of the synergy between the FGFR and the MDM2 antagonists. We confirmed the inhibitory effect of erdafitinib on tumor growth using a DDLPS xenograft model. Finally and importantly, we report the efficacy of FGFR inhibition in two metastatic DDLPS patients heavily pretreated and refractory to several lines of treatment with notably one patient on erdafitinib showing stable disease for 15 weeks. In conclusion, we have shown that the FGFR pathway has therapeutic potential for a subset of DDLPS patients and that FGFR expression might constitute a powerful biomarker to select patients for clinical trials testing FGFR inhibitors. Citation Format: Bérengère Dadone-Montaudié, Audrey Laroche-Clary, Aline Mongis, Vanessa Chaire, Ilaria Di Mauro, Renaud Schiappa, Emmanuel Chamorey, Bertucci François, Florence Pedeutour, Finetti Pascal, Jean-François Michiels, Antoine Italiano, Laurence Bianchini. Analysis of the role of FGFR signaling in liposarcomas: Dual targeting of FGFR and MDM2 is synergistic [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5185.