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Supplementary Table S4 from Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies

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posted on 2024-11-01, 07:21 authored by Francesco Facchinetti, Yohann Loriot, Floriane Brayé, Damien Vasseur, Rastislav Bahleda, Ludovic Bigot, Rémy Barbé, Catline Nobre, David Combarel, Stefan Michiels, Antoine Italiano, Cristina Smolenschi, Lambros Tselikas, Jean-Yves Scoazec, Santiago Ponce-Aix, Benjamin Besse, Fabrice André, Ken A. Olaussen, Antoine Hollebecque, Luc Friboulet

Outcomes among patients suffering from intrahepatic cholangiocarcinoma, treated with either reversible FGFR inhibitors or the irreversible agent futibatinib.

Funding

European Research Council (ERC)

Fondation Philanthropia (Philanthropia Foundation)

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ARTICLE ABSTRACT

Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies. We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing 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 xenograft models were used for functional studies. Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and 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 benefited from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y. At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and interpatient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors.