A systems biology approach to define mechanisms, phenotypes, and drivers in PanNETs with a personalized perspective.
Journal
NPJ systems biology and applications
ISSN: 2056-7189
Titre abrégé: NPJ Syst Biol Appl
Pays: England
ID NLM: 101677786
Informations de publication
Date de publication:
03 06 2023
03 06 2023
Historique:
received:
12
12
2022
accepted:
17
05
2023
medline:
5
6
2023
pubmed:
4
6
2023
entrez:
3
6
2023
Statut:
epublish
Résumé
Pancreatic neuroendocrine tumors (PanNETs) are a rare tumor entity with largely unpredictable progression and increasing incidence in developed countries. Molecular pathways involved in PanNETs development are still not elucidated, and specific biomarkers are missing. Moreover, the heterogeneity of PanNETs makes their treatment challenging and most approved targeted therapeutic options for PanNETs lack objective responses. Here, we applied a systems biology approach integrating dynamic modeling strategies, foreign classifier tailored approaches, and patient expression profiles to predict PanNETs progression as well as resistance mechanisms to clinically approved treatments such as the mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We set up a model able to represent frequently reported PanNETs drivers in patient cohorts, such as Menin-1 (MEN1), Death domain associated protein (DAXX), Tuberous Sclerosis (TSC), as well as wild-type tumors. Model-based simulations suggested drivers of cancer progression as both first and second hits after MEN1 loss. In addition, we could predict the benefit of mTORC1 inhibitors on differentially mutated cohorts and hypothesize resistance mechanisms. Our approach sheds light on a more personalized prediction and treatment of PanNET mutant phenotypes.
Identifiants
pubmed: 37270586
doi: 10.1038/s41540-023-00283-8
pii: 10.1038/s41540-023-00283-8
pmc: PMC10239456
doi:
Substances chimiques
Nuclear Proteins
0
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
22Informations de copyright
© 2023. The Author(s).
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