Understanding and Overcoming Resistance to Selective FGFR inhibitors Across FGFR2-Driven Malignancies.
Clin Cancer Res
; 2024 Sep 03.
Article
en En
| MEDLINE
| ID: mdl-39226398
ABSTRACT
PURPOSE:
Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies. EXPERIMENTALDESIGN:
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. FGFR2BICC1 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 intra- and inter-patient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly-oriented treatment strategies across FGFR2-driven tumors.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2024
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Estados Unidos