Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy

Cold Spring Harbor Molecular Case Studies
Melanie A KrookSameek Roychowdhury

Abstract

Cholangiocarcinoma is a highly aggressive and lethal malignancy, with limited treatment options available. Recently, FGFR inhibitors have been developed and utilized in FGFR-mutant cholangiocarcinoma; however, resistance often develops and the genomic determinants of resistance are not fully characterized. We completed whole-exome sequencing (WES) of 11 unique tumor samples obtained from a rapid research autopsy on a patient with FGFR-fusion-positive cholangiocarcinoma who initially responded to the pan-FGFR inhibitor, INCB054828. In vitro studies were carried out to characterize the novel FGFR alteration and secondary FGFR2 mutation identified. Multisite WES and analysis of tumor heterogeneity through subclonal inference identified four genetically distinct cancer cell populations, two of which were only observed after treatment. Additionally, WES revealed an FGFR2 N549H mutation hypothesized to confer resistance to the FGFR inhibitor INCB054828 in a single tumor sample. This hypothesis was corroborated with in vitro cell-based studies in which cells expressing FGFR2-CLIP1 fusion were sensitive to INCB054828 (IC50 value of 10.16 nM), whereas cells with the addition of the N549H mutation were resistant to INCB054828 (IC50 value...Continue Reading

Associated Clinical Trials

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Datasets Mentioned

BETA
SCV000927106
SCV000914229.1

Methods Mentioned

BETA
biopsies
biopsy
surgical resection
reverse transcription PCR
surgical
exome sequencing
single-cell sequencing
PCR

Clinical Trials Mentioned

NCT02393248
NCT02090530

Software Mentioned

COSMIC
Interactive Tree of Life ( iTOL )
RapidNJ
Prism
Burrows Aligner ( bwa )
R package BradleyTerryScalable
MANTIS
Picard
Canopy
FoundationOne

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