Combined Targeting of Pathogenetic Mechanisms in Pancreatic Neuroendocrine Tumors Elicits Synergistic Antitumor Effects.
buparlisib
combination therapy
pancreatic NETs
primary human tumoroids
ribociclib
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
08 Nov 2022
08 Nov 2022
Historique:
received:
12
10
2022
revised:
01
11
2022
accepted:
03
11
2022
entrez:
26
11
2022
pubmed:
27
11
2022
medline:
27
11
2022
Statut:
epublish
Résumé
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 (
Identifiants
pubmed: 36428573
pii: cancers14225481
doi: 10.3390/cancers14225481
pmc: PMC9688197
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : 314061271-TRR 205-B11
Organisme : German Cancer Aid
ID : 70113629
Organisme : Wilhelm Sander Stiftung
ID : 2017.073.2 and 2017.012.1
Organisme : Swiss Cancer Research Foundation
ID : KFS-4227-08-2017
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