Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance

PLoS Comput Biol. 2021 Nov 4;17(11):e1009515. doi: 10.1371/journal.pcbi.1009515. eCollection 2021 Nov.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Feedback*
  • Humans
  • MAP Kinase Signaling System
  • Models, Biological*
  • Neuroblastoma / drug therapy
  • Neuroblastoma / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Receptor, IGF Type 1 / metabolism
  • Receptor, IGF Type 2 / metabolism
  • Signal Transduction*

Substances

  • Protein Kinase Inhibitors
  • Receptor, IGF Type 2
  • Receptor, IGF Type 1

Grant support

We acknowledge funding from the Berlin Institute of Health (CRG1 Terminate NB) and from the Federal Ministry of Education and Research /BMBF/ (grant MSTARS, to NB and MS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.