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Gulde, S. ; Foscarini, A. ; April-Monn, S.L.* ; Genio, E. ; Marangelo, A. ; Satam, S. ; Helbling, D.* ; Falconi, M.* ; Toledo, R.A.* ; Schrader, J.* ; Perren, A.* ; Marinoni, I.* ; Pellegata, N.S.

Combined targeting of pathogenetic mechanisms in pancreatic neuroendocrine tumors elicits synergistic antitumor effects.

Cancers 14:5481 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Pancreatic neuroendocrine neoplasms (PanNENs) are the second most common malignancy of the pancreas. Surgery remains the only curative treatment for localized disease. For patients with inoperable advanced or metastatic disease, few targeted therapies are available, but their efficacy is unpredictable and variable. Exploiting prior knowledge on pathogenetic processes involved in PanNEN tumorigenesis, we tested buparlisib (PI3K inhibitor) and ribociclib (CDK4/6 inhibitor), as single agents or in combination, in different preclinical models. First, we used cell lines representative of well-differentiated (INS-1E, NT-3) and poorly differentiated (BON-1) PanNENs. The combination of buparlisib with ribociclib reduced the proliferation of 2D and 3D spheroid cultures more potently than the individual drugs. Buparlisib, but not ribociclib, induced apoptosis. The anti-proliferative activity of the drugs correlated with downstream target inhibition at mRNA and protein levels. We then tested the drugs on primary islet microtissues from a genetic PanNET animal model (Men1-defective mice) and from wild-type mice: the drug combination was effective against the former without altering islet cell physiology. Finally, we treated PanNET patient-derived islet-like 3D tumoroids: the combination of buparlisib with ribociclib was effective in three out of four samples. Combined targeting of PI3K and CDK4/6 is a promising strategy for PanNENs spanning various molecular and histo-pathological features.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Buparlisib ; Combination Therapy ; Pancreatic Nets ; Primary Human Tumoroids ; Ribociclib
ISSN (print) / ISBN 2072-6694
Journal Cancers
Quellenangaben Volume: 14, Issue: 22, Pages: , Article Number: 5481 Supplement: ,
Publisher MDPI
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
Grants Swiss Cancer Research Foundation
Deutsche Krebshilfe
Deutsche Forschungsgemeinschaft
Wilhelm Sander-Stiftung