Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance.
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Drug Screening Assays, Antitumor
Feedback
Humans
MAP Kinase Signaling System
Models, Biological
Neuroblastoma
/ drug therapy
Protein Kinase Inhibitors
/ pharmacology
Receptor, IGF Type 1
/ metabolism
Receptor, IGF Type 2
/ metabolism
Signal Transduction
Journal
PLoS computational biology
ISSN: 1553-7358
Titre abrégé: PLoS Comput Biol
Pays: United States
ID NLM: 101238922
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
07
06
2021
accepted:
01
10
2021
revised:
19
11
2021
pubmed:
5
11
2021
medline:
31
12
2021
entrez:
4
11
2021
Statut:
epublish
Résumé
Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms. We found that negative feedbacks within MAPK signalling and via the IGF receptor mediate re-activation of MAPK signalling upon treatment in resistant cell lines. By using cell-line specific models, we predict that combinations of MEK inhibitors with RAF or IGFR inhibitors can overcome resistance, and tested these predictions experimentally. In addition, phospho-proteomic profiling confirmed the cell-specific feedback effects and synergy of MEK and IGFR targeted treatment. Our study shows that a quantitative understanding of signalling and feedback mechanisms facilitated by models can help to develop and optimise therapeutic strategies. Our findings should be considered for the planning of future clinical trials introducing MEKi in the treatment of neuroblastoma.
Identifiants
pubmed: 34735429
doi: 10.1371/journal.pcbi.1009515
pii: PCOMPBIOL-D-21-01059
pmc: PMC8604339
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Receptor, IGF Type 2
0
Receptor, IGF Type 1
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009515Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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