Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies.
Intrahepatic cholangiocarcinoma (ICC) remains a deadly malignancy lacking systemic therapies for advanced disease. Recent advancements include selective FGFR1-3 inhibitors for the 15% of ICC patients harboring fusions, although survival is limited by poor response and resistance. Herein we report generation of a patient-derived FGFR2 fusion-positive ICC model system consisting of a cell line, organoid, and xenograft, which have undergone complete histologic, genomic, and phenotypic characterization, including testing standard-of-care systemic therapies. Using these FGFR2 fusion-positive ICC models, we conducted an unbiased high-throughput small molecule screen to prioritize combination strategies with FGFR inhibition, from which HDAC inhibition together with pemigatinib was validated in vitro and in vivo as a synergistic therapy for ICC. Additionally, we demonstrate broad utility of the FGFR/HDAC combination for other FGFR fusion-positive solid tumors. These data are directly translatable and justify early phase trials to establish dosing, safety, and therapeutic efficacy of this synergistic combination.
Duke Scholars
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- 3211 Oncology and carcinogenesis
- 3204 Immunology
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- 3211 Oncology and carcinogenesis
- 3204 Immunology