Data from Resistance to selective FGFR inhibitors in FGFR-driven urothelial cancer
Year: 2024
Type: other
Abstract: Several FGFR inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 FGFR-driven urothelial cancer patients treated with selective FGFR inhibitors and analyzed post-progression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 5 TSC1/2, n = 5 PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergic with pictilisib in the presence of PIK3CA E545K, while erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation.
Authors: Francesco Facchinetti, Antoine Hollebecque, Floriane Braye, Damien Vasseur, Yoann Pradat, Rastislav Bahleda, Cedric Pobel, Ludovic Bigot, Olivier Deas, Juan David Florez Arango, Giorgia Guaitoli, Hayato Mizuta, David Combarel, Lambros Tselikas, Stefan Michiels, Sergey I. Nikolaev, Jean-Yves Scoazec, Santiago Ponce-Aix, Benjamin Besse, Ken A. Olaussen, Yohann Loriot, Luc Friboulet
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402806399