Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance 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 to 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, phospo-proteomics profiles confirm the cell-specific feedback effects and synergy of MEK and IGFR targeted treatements. Our study shows that a quantitative understanding of signalling and feedback mechanisms facilitated by models can help to develop and optimise therapeutic strategies, and our findings should be considered for the planning of future clinical trials introducing MEKi in the treatment of neuroblastoma.
19
The categories of this paper are: epidemiology
30
The categories of this paper are: scientific
7
The categories of this paper are: ecology
17
The categories of this paper are: molecular
18
The categories of this paper are: systems
15
The categories of this paper are: developmental
28
The categories of this paper are: communication
26
The categories of this paper are: biochemistry
6
The categories of this paper are: plant
13
The categories of this paper are: animal
11
The categories of this paper are: cognition
8
The categories of this paper are: genomics
1
The categories of this paper are: bioinformatics
29
The categories of this paper are: education
5
The categories of this paper are: cell
25
The categories of this paper are: bioengineering