Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies

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.