Faculty Collaboration Database

Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy. Cold Spring Harb Mol Case Stud 2019 Aug;5(4)

Date

08/03/2019

Pubmed ID

31371345

Pubmed Central ID

PMC6672025

DOI

10.1101/mcs.a004002

Scopus ID

2-s2.0-85070757277 (requires institutional sign-in at Scopus site)   55 Citations

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 of 1527.57 nM). Furthermore, the FGFR2 N549H secondary mutation displayed cross-resistance to other selective FGFR inhibitors, but remained sensitive to the nonselective inhibitor, ponatinib. Rapid research autopsy has the potential to provide unprecedented insights into the clonal evolution of cancer throughout the course of the disease. In this study, we demonstrate the emergence of a drug resistance mutation and characterize the evolution of tumor subclones within a cholangiocarcinoma disease course.

Author List

Krook MA, Bonneville R, Chen HZ, Reeser JW, Wing MR, Martin DM, Smith AM, Dao T, Samorodnitsky E, Paruchuri A, Miya J, Baker KR, Yu L, Timmers C, Dittmar K, Freud AG, Allenby P, Roychowdhury S

Author

Hui-Zi Chen MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Autopsy
Cell Line, Tumor
Cholangiocarcinoma
Clonal Evolution
Drug Resistance, Neoplasm
Humans
Male
Middle Aged
Morpholines
Mutation
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Receptor, Fibroblast Growth Factor, Type 2