Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Apoptosis
/ drug effects
Cell Differentiation
/ drug effects
Cell Line, Tumor
Cell Movement
/ drug effects
Female
Humans
Mice, Nude
N-Myc Proto-Oncogene Protein
/ metabolism
Neuroblastoma
/ drug therapy
Phosphatidylinositol 3-Kinase
/ metabolism
Phosphoinositide-3 Kinase Inhibitors
/ pharmacology
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Proto-Oncogene Proteins
/ antagonists & inhibitors
Pyridines
/ pharmacology
Pyrimidines
/ pharmacology
Signal Transduction
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Thiophenes
/ pharmacology
Tumor Burden
Xenograft Model Antitumor Assays
IBL-302
PI3K
cisplatin
multikinase inhibition
neuroblastoma
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
12
11
2018
revised:
04
06
2019
accepted:
24
06
2019
pubmed:
17
7
2019
medline:
6
5
2020
entrez:
17
7
2019
Statut:
ppublish
Résumé
The PI3K pathway is a major driver of cancer progression. However, clinical resistance to PI3K inhibition is common. IBL-302 is a novel highly specific triple PIM, PI3K, and mTOR inhibitor. Screening IBL-302 in over 700 cell lines representing 47 tumor types identified neuroblastoma as a strong candidate for PIM/PI3K/mTOR inhibition. IBL-302 was more effective than single PI3K inhibition in vitro, and IBL-302 treatment of neuroblastoma patient-derived xenograft (PDX) cells induced apoptosis, differentiated tumor cells, and decreased N-Myc protein levels. IBL-302 further enhanced the effect of the common cytotoxic chemotherapies cisplatin, doxorubicin, and etoposide. Global genome, proteome, and phospho-proteome analyses identified crucial biological processes, including cell motility and apoptosis, targeted by IBL-302 treatment. While IBL-302 treatment alone reduced tumor growth in vivo, combination therapy with low-dose cisplatin inhibited neuroblastoma PDX growth. Complementing conventional chemotherapy treatment with PIM/PI3K/mTOR inhibition has the potential to improve clinical outcomes and reduce severe late effects in children with high-risk neuroblastoma.
Identifiants
pubmed: 31310053
doi: 10.15252/emmm.201810058
pmc: PMC6685085
doi:
Substances chimiques
IBL-302
0
MYCN protein, human
0
N-Myc Proto-Oncogene Protein
0
Phosphoinositide-3 Kinase Inhibitors
0
Proto-Oncogene Proteins
0
Pyridines
0
Pyrimidines
0
Thiophenes
0
MTOR protein, human
EC 2.7.1.1
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
PIM3 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Banques de données
GEO
['GSE133137']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e10058Subventions
Organisme : Swedish Research Council
Pays : International
Organisme : Cancerfonden (Swedish Cancer Society)
Pays : International
Organisme : Barncancerfonden (Swedish Childhood Cancer Foundation)
Pays : International
Organisme : Region Skåne
Pays : International
Organisme : Research Funds of Skåne University Hospital
Pays : International
Organisme : Mary Bevé Foundation
Pays : International
Organisme : Magnus Bergvalls stiftelse
Pays : International
Organisme : Thelma Zoéga Foundation
Pays : International
Organisme : Hans von Kantzow Foundation
Pays : International
Organisme : Crafoord Foundation
Pays : International
Organisme : Åke Wiberg Foundation
Pays : International
Organisme : Jeanssons Stiftelser
Pays : International
Organisme : Ollie och Elof Ericssons stiftelser
Pays : International
Organisme : Berth von Kantzows stiftelse
Pays : International
Organisme : Royal Physiographic Society of Lund
Pays : International
Organisme : Spanish Ministry of Health and Social Policy
ID : ADE08/90038
Pays : International
Organisme : Spanish Ministry of Science and Innovation
ID : CIT-090000-2008-14
Pays : International
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
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