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Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies
Francesco Facchinetti1, Yohann Loriot1,2,3, Floriane Brayé1
1Université Paris-Saclay, Gustave Roussy, Inserm U981, Villejuif, France.
Purpose:
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, ± 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.
Results:
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.
Conclusions:
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.
Insights
Resistance to FGFR inhibitors in FGFR2-driven cancers shows significant molecular diversity, especially in cholangiocarcinoma. Sequential, targeted treatments can overcome this resistance, improving patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Fibroblast Growth Factor Receptor 2 (FGFR2) alterations drive various malignancies, including cholangiocarcinoma.
- Selective FGFR inhibitors offer targeted therapy but acquired resistance limits long-term efficacy.
- Understanding resistance mechanisms is critical for developing effective treatment strategies.
Purpose of the Study:
- To investigate the molecular mechanisms of acquired resistance to selective FGFR inhibitors in patients with FGFR2-driven malignancies.
- To analyze the heterogeneity of resistance mutations and identify potential therapeutic vulnerabilities.
Main Methods:
- Analysis of sequential circulating tumor DNA (ctDNA) and tissue biopsies from patients with FGFR2 alterations progressing on pan-FGFR inhibitors.
- Whole-exome sequencing and targeted next-generation sequencing were employed.
- Functional validation using FGFR2::BICC1 Ba/F3 and patient-derived xenograft (PDX) models.
Main Results:
- High intra- and interpatient molecular heterogeneity was observed, particularly polyclonal FGFR2 kinase domain mutations in cholangiocarcinoma (14/27 patients) at resistance to both reversible and irreversible inhibitors.
- Other tumor types showed less polyclonality. Resistance mutations targeted key residues like N550 and V565.
- Off-target alterations in PI3K/mTOR and MAPK pathways were common. Irreversible inhibitors demonstrated better activity against FGFR2 mutations, with lirafugratinib effective against V565 mutations.
Conclusions:
- FGFR2-driven malignancies exhibit significant molecular heterogeneity upon progression to FGFR inhibitors.
- Sequential, molecularly guided treatment strategies hold promise for overcoming resistance in these tumors.
- Targeted therapies, including irreversible inhibitors and pathway-specific agents, can be effective in managing resistance.
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