PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus.
Acrylamides
/ pharmacology
Aminopyridines
/ pharmacology
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Cell Proliferation
Cytokines
/ antagonists & inhibitors
Drug Therapy, Combination
Everolimus
/ pharmacology
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Mice
Mice, Inbred ICR
Mice, SCID
Neuroendocrine Tumors
/ drug therapy
Nicotinamide Phosphoribosyltransferase
/ antagonists & inhibitors
Pancreatic Neoplasms
/ drug therapy
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
p21-Activated Kinases
/ antagonists & inhibitors
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
22
12
2020
revised:
12
06
2021
accepted:
08
07
2021
pubmed:
14
7
2021
medline:
11
2
2022
entrez:
13
7
2021
Statut:
ppublish
Résumé
Metastatic pancreatic neuroendocrine tumors (PNET) remain an unmet clinical problem. Chronologic treatment in PNETs includes observation (watchful protocol), surgery, targeted therapy, and chemotherapy. However, increasing evidence illustrates that the outcomes of targeted therapeutic options for the treatment of advanced PNETs show minimal response. The FDA-approved mTOR inhibitor everolimus does not shrink these tumors. It only delays disease progression in a subset of patients, while a significant fraction acquires resistance and shows disease progression. Thus, there is a need for more effective targeted approaches to sensitize PNETs to everolimus for better treatment outcomes. Previously, we showed that mTOR regulator p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyl transferase (NAMPT) were aberrantly expressed in PNET tissue and promoted everolimus resistance. In this report, we demonstrate that PAK4-NAMPT dual inhibitor KPT-9274 can synergize with everolimus (growth inhibition, colony suppression, and glucose uptake assays). KPT-9274-everolimus disrupted spheroid formation in multiple PNET models. Molecular analysis showed alteration of mTORC2 through downregulation of RICTOR as a mechanism supporting synergy with everolimus
Identifiants
pubmed: 34253597
pii: 1535-7163.MCT-20-1105
doi: 10.1158/1535-7163.MCT-20-1105
pmc: PMC8492493
mid: NIHMS1725466
doi:
Substances chimiques
Acrylamides
0
Aminopyridines
0
Antineoplastic Agents
0
Cytokines
0
KPT-9274
0
Everolimus
9HW64Q8G6G
Nicotinamide Phosphoribosyltransferase
EC 2.4.2.12
nicotinamide phosphoribosyltransferase, human
EC 2.4.2.12
PAK4 protein, human
EC 2.7.1.11
p21-Activated Kinases
EC 2.7.11.1
Banques de données
ClinicalTrials.gov
['NCT00932126', 'NCT02702492']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1836-1845Subventions
Organisme : NCI NIH HHS
ID : P30 CA022453
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA240607
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009531
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
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