Growth factor signaling predicts therapy resistance mechanisms and defines neuroblastoma subtypes.
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Drug Resistance, Neoplasm
Erythropoietin
/ genetics
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Mutation
Neoplasm Staging
Nerve Growth Factor
/ genetics
Neuroblastoma
/ drug therapy
Protein Kinase Inhibitors
/ pharmacology
Signal Transduction
/ drug effects
Survival Analysis
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
04
03
2021
accepted:
10
09
2021
revised:
25
08
2021
pubmed:
25
9
2021
medline:
30
12
2021
entrez:
24
9
2021
Statut:
ppublish
Résumé
Neuroblastoma (NB) has a low frequency of recurrent mutations compared to other cancers, which hinders the development of targeted therapies and novel risk stratification strategies. Multikinase inhibitors have shown potential in treating high-risk NB, but their efficacy is likely impaired by the cancer cells' ability to adapt to these drugs through the employment of alternative signaling pathways. Based on the expression of 48 growth factor-related genes in 1189 NB tumors, we have developed a model for NB patient survival prediction. This model discriminates between stage 4 NB tumors with favorable outcomes (>80% overall survival) and very poor outcomes (<10%) independently from MYCN-amplification status. Using signaling pathway analysis and gene set enrichment methods in 60 NB patients with known therapy response, we identified signaling pathways, including EPO, NGF, and HGF, upregulated in patients with no or partial response. In a therapeutic setting, we showed that among six selected growth factors, EPO, and NGF showed the most pronounced protective effects in vitro against several promising anti-NB multikinase inhibitors: imatinib, dasatinib, crizotinib, cabozantinib, and axitinib. Mechanistically kinase inhibitors potentiated NB cells to stronger ERK activation by EPO and NGF. The protective action of these growth factors strongly correlated with ERK activation and was ERK-dependent. ERK inhibitors combined with anticancer drugs, especially with dasatinib, showed a synergistic effect on NB cell death. Consideration of growth factor signaling activity benefits NB outcome prediction and tailoring therapy regimens to treat NB.
Identifiants
pubmed: 34556815
doi: 10.1038/s41388-021-02018-7
pii: 10.1038/s41388-021-02018-7
pmc: PMC8566230
doi:
Substances chimiques
EPO protein, human
0
NGF protein, human
0
Protein Kinase Inhibitors
0
Erythropoietin
11096-26-7
Nerve Growth Factor
9061-61-4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6258-6272Informations de copyright
© 2021. The Author(s).
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