Abstract 5288: Mechanisms of resistance to FGFR inhibitors in urothelial cancer cell lines and patients harboring FGFR3 alterations and strategies to overcome it

Introduction The Fibroblast Growth Factor Receptor (FGFR) has become a key target in urothelial cancer. The FGFR inhibitor (FGFRi) erdafitinib has been approved for clinical use and many others are in development. Unfortunately, responses have shown to last short. Thus, it is urgently required to identify the underlying mechanisms of resistance and establish strategies to overcome it. We designed a comprehensive in vitro study in FGFR3-altered urothelial cancer cell lines after acquiring resistance to FGFRis. In parallel, we monitored the clinical and molecular evolution (through tumor biopsies and ctDNA) of three patients treated with FGFRi at our institution. Experimental Procedures Drug sensitivity to FGFRi (Erdafitinib and AZD4547) was evaluated in bladder cancer cell lines harboring FGFR3 point mutations (pS249C) or rearrangements (FGFR3/BAIAP2L1 or TACC3). After performing 7-days proliferation assays, cell lines showing nM-range sensitivity were long-term treated with high concentrations of both compounds to induce therapeutic resistance. Cell lysates were collected and protein arrays (Human Phospho-RTK and Kinases Array, RD 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5288.