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Article Dans Une Revue Cancer Discovery Année : 2023

Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer

Olivier Déas
  • Fonction : Auteur

Résumé

Several fibroblast growth factor receptor (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 patients with FGFR-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression 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, and L608V). Using Ba/F3 cells, we defined their spectrum of resist-ance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K–mTOR pathway (n = 4 TSC1/2, n = 4 PIK3CA, n = 1 TSC1 and PIK3CA, n = 1 NF2, n = 1 PTEN). In patientderived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib–gefitinib combination was able to overcome bypass resistance mediated by EGFR activation. SIGNIFICANCE: In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K–mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance.

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hal-04229568 , version 1 (05-10-2023)

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Francesco Facchinetti, Antoine Hollebecque, Floriane Braye, Damien Vasseur, Yoann Pradat, et al.. Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer. Cancer Discovery, 2023, 13 (9), pp.1998-2011. ⟨10.1158/2159-8290.CD-22-1441⟩. ⟨hal-04229568⟩
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