Combined Targeting of Pathogenetic Mechanisms in Pancreatic Neuroendocrine Tumors Elicits Synergistic Antitumor Effects.

Gulde, Sebastian; Foscarini, Alessia; April-Monn, Simon L; Genio, Edoardo; Marangelo, Alessandro; Satam, Swapna; Helbling, Daniel; Falconi, Massimo; Toledo, Rodrigo A; Schrader, Jörg; Perren, Aurel; Marinoni, Ilaria; Pellegata, Natalia S (2022). Combined Targeting of Pathogenetic Mechanisms in Pancreatic Neuroendocrine Tumors Elicits Synergistic Antitumor Effects. Cancers, 14(22) MDPI AG 10.3390/cancers14225481

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

April-Monn, Simon; Perren, Aurel and Marinoni, Ilaria

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2072-6694

Publisher:

MDPI AG

Language:

English

Submitter:

Pubmed Import

Date Deposited:

28 Nov 2022 13:11

Last Modified:

05 Dec 2022 16:29

Publisher DOI:

10.3390/cancers14225481

PubMed ID:

36428573

Uncontrolled Keywords:

buparlisib combination therapy pancreatic NETs primary human tumoroids ribociclib

BORIS DOI:

10.48350/175197

URI:

https://boris.unibe.ch/id/eprint/175197

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