Understanding and Overcoming Resistance to Selective FGFR inhibitors Across FGFR2-Driven Malignancies - Centre de recherche en Épidémiologie et Santé des Populations
Article Dans Une Revue Clinical Cancer Research Année : 2024

Understanding and Overcoming Resistance to Selective FGFR inhibitors Across FGFR2-Driven Malignancies

Francesco Facchinetti
Yohann Loriot
Floriane Brayé
Damien Vasseur
Rastislav Bahleda
Ludovic Bigot
Rémy Barbé
Catline Nobre
David Combarel
Antoine Italiano
Cristina Smolenschi
Lambros Tselikas
Jean-Yves Scoazec
Santiago Ponce- Aix
  • Fonction : Auteur
Benjamin Besse
Fabrice André
Ken A Olaussen
Antoine Hollebecque
F Hoffmann-La
  • Fonction : Auteur
Roche Ltd
  • Fonction : Auteur

Résumé

Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies.

Experimental Design

We analyzed sequential ctDNA, +/-WES or targeted NGS on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenografts (PDX) models were used for functional studies.

Results

Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g. pemigatinib, erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated; after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefitted from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on PDX, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y.

Conclusions

At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intraand inter-patient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly-oriented treatment strategies across FGFR2driven tumors.

Fichier principal
Vignette du fichier
FGFR2 resistance CCR 2024.pdf (2.25 Mo) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-04692700 , version 1 (10-09-2024)

Identifiants

Citer

Francesco Facchinetti, Yohann Loriot, Floriane Brayé, Damien Vasseur, Rastislav Bahleda, et al.. Understanding and Overcoming Resistance to Selective FGFR inhibitors Across FGFR2-Driven Malignancies. Clinical Cancer Research, 2024, ⟨10.1158/1078-0432.CCR-24-1834/3492985/ccr-24-1834.pdf⟩. ⟨hal-04692700⟩
0 Consultations
0 Téléchargements

Altmetric

Partager

More