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

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 charact...

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Bibliographic Details
Published in:	Cold Spring Harbor molecular case studies 2019-08, Vol.5 (4), p.a004002
Main Authors:	Krook, Melanie A, Bonneville, Russell, Chen, Hui-Zi, Reeser, Julie W, Wing, Michele R, Martin, Dorrelyn M, Smith, Amy M, Dao, Thuy, Samorodnitsky, Eric, Paruchuri, Anoosha, Miya, Jharna, Baker, Kaitlin R, Yu, Lianbo, Timmers, Cynthia, Dittmar, Kristin, Freud, Aharon G, Allenby, Patricia, Roychowdhury, Sameek
Format:	Article
Language:	eng
Subjects:	Autopsies Autopsy Cancer Cell fusion Cholangiocarcinoma Cross-resistance Drug resistance Evolution Fibroblast growth factor receptor 2 Fibroblast growth factor receptors Heterogeneity Inhibitors Malignancy Mutation Tumors
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Summary:	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 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 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 fusion were sensitive to INCB054828 (IC value of 10.16 nM), whereas cells with the addition of the N549H mutation were resistant to INCB054828 (IC value of 1527.57 nM). Furthermore, the 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.
ISSN:	2373-2865 2373-2873