Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies

Author:

Lidsky Michael E.ORCID,Wang ZechenORCID,Lu Min,Liu AnnieORCID,Hsu S. DavidORCID,McCall Shannon J.,Sheng Zhecheng,Granek Joshua A.ORCID,Owzar Kouros,Anderson Karen S.,Wood Kris C.ORCID

Abstract

AbstractIntrahepatic 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.

Funder

Cholangiocarcinoma Foundation

U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences

Duke Department of Surgery; Duke Cancer Institute; Duke School of Medicine Strong Start Award; American College of Surgeons National Surgeon Scientist Program

U.S. Department of Health & Human Services | NIH | National Cancer Institute

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology

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