Faculty, Staff and Student Publications
Publication Date
10-2-2024
Journal
Molecular Therapy
Abstract
Patients with cancer of unknown primary (CUP) carry the double burden of an aggressive disease and reduced access to therapies. Experimental models are pivotal for CUP biology investigation and drug testing. We derived two CUP cell lines (CUP#55 and #96) and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines and PDXs underwent histological, immune-phenotypical, molecular, and genomic characterization confirming the features of the original tumor. The tissue-of-origin prediction was obtained from the tumor microRNA expression profile and confirmed by single-cell transcriptomics. Genomic testing and fluorescence in situ hybridization analysis identified FGFR2 gene amplification in both models, in the form of homogeneously staining region (HSR) in CUP#55 and double minutes in CUP#96. FGFR2 was recognized as the main oncogenic driver and therapeutic target. FGFR2-targeting drug BGJ398 (infigratinib) in combination with the MEK inhibitor trametinib proved to be synergic and exceptionally active, both in vitro and in vivo. The effects of the combined treatment by single-cell gene expression analysis revealed a remarkable plasticity of tumor cells and the greater sensitivity of cells with epithelial phenotype. This study brings personalized therapy closer to CUP patients and provides the rationale for FGFR2 and MEK targeting in metastatic tumors with FGFR2 pathway activation.
Keywords
Animals, Female, Humans, Mice, Cell Line, Tumor, Drug Synergism, Gene Amplification, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Neoplasms, Unknown Primary, Phenylurea Compounds, Protein Kinase Inhibitors, Pyridones, Pyrimidines, Pyrimidinones, Receptor, Fibroblast Growth Factor, Type 2, Xenograft Model Antitumor Assays, cancer of unknown primary, CUP, occult primary tumors, patient-derived xenografts, liquid biopsy, FGFR2, FGFR2 inhibitor, MEK inhibitor, infigratinib, trametinib
DOI
10.1016/j.ymthe.2024.07.011
PMID
39033323
PMCID
PMC11489551
PubMedCentral® Posted Date
7-20-2024
PubMedCentral® Full Text Version
Post-print
Graphical Abstract
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons