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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lidsky, ME; Wang, Z; Lu, M; Liu, A; Hsu, SD; McCall, SJ; Sheng, Z; Granek, JA; Owzar, K; Anderson, KS; Wood, KC

Published Date

  • October 23, 2022

Published In

Volume / Issue

  • 6 / 1

Start / End Page

  • 75 -

PubMed ID

  • 36274097

Pubmed Central ID

  • PMC9588766

International Standard Serial Number (ISSN)

  • 2397-768X

Digital Object Identifier (DOI)

  • 10.1038/s41698-022-00320-5


  • eng

Conference Location

  • England