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Ref Type Journal Article
PMID (39033323)
Authors Cavazzoni A, Salamon I, Fumarola C, Gallerani G, Laprovitera N, Gelsomino F, Riefolo M, Rihawi K, Porcellini E, Rossi T, Mazzeschi M, Naddeo M, Serravalle S, Broseghini E, Agostinis F, Deas O, Roncarati R, Durante G, Pace I, Lauriola M, Garajova I, Calin GA, Bonafè M, D'Errico A, Petronini PG, Cairo S, Ardizzoni A, Sales G, Ferracin M
Title Synergic activity of FGFR2 and MEK inhibitors in the treatment of FGFR2-amplified cancers of unknown primary.
Journal Vol Issue Date Pages Journal Short Title
Molecular therapy : the journal of the American Society of Gene Therapy 2024 Jul 19 Mol Ther
URL
Abstract Text 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 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 amp Cancer of Unknown Primary sensitive Infigratinib + Trametinib Preclinical - Pdx & cell culture Actionable In a preclinical study, the combination of Truseltiq (infigratinib) and Mekinist (trametinib) inhibited Akt and Mapk signaling, induced apoptosis, and synergistically decreased proliferation in FGFR2-amplified cell lines derived from patients with cancer of unknown primary in culture and decreased tumor volume in patient-derived xenograft (PDX) models (PMID: 39033323). 39033323