作者
Andrea Cavazzoni,Irene Salamon,Claudia Fumarola,Giulia Gallerani,Noemi Laprovitera,Francesco Gelsomino,Mattia Riefolo,Karim Rihawi,Elisa Porcellini,Tania Rossi,Martina Mazzeschi,Maria Naddeo,Salvatore Serravalle,Elisabetta Broseghini,Federico Agostinis,Olivier Déas,Roberta Roncarati,Giorgio Durante,Mattia Lauriola,Ingrid Garajovà,George A. Călin,Massimiliano Bonafè,Antonietta D’Errico,Pier Giorgio Petronini,Stefano Cairo,Andrea Ardizzoni,Gabriele Sales,Manuela Ferracin
摘要
Abstract Patients with cancer of unknown primary (CUP) carry the 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 FISH analysis identified FGFR2 gene amplification in both models, in the form of homogenously 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 BGJ-398 (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.