Quantifying ERK activity in response to inhibition of the BRAFV600E-MEK-ERK cascade using mathematical modelling.
Br J Cancer
; 125(11): 1552-1560, 2021 11.
Article
en En
| MEDLINE
| ID: mdl-34621046
ABSTRACT
BACKGROUND:
Simultaneous inhibition of multiple components of the BRAF-MEK-ERK cascade (vertical inhibition) has become a standard of care for treating BRAF-mutant melanoma. However, the molecular mechanism of how vertical inhibition synergistically suppresses intracellular ERK activity, and consequently cell proliferation, are yet to be fully elucidated.METHODS:
We develop a mechanistic mathematical model that describes how the mutant BRAF inhibitor, dabrafenib, and the MEK inhibitor, trametinib, affect BRAFV600E-MEK-ERK signalling. The model is based on a system of chemical reactions that describes cascade signalling dynamics. Using mass action kinetics, the chemical reactions are re-expressed as ordinary differential equations that are parameterised by in vitro data and solved numerically to obtain the temporal evolution of cascade component concentrations.RESULTS:
The model provides a quantitative method to compute how dabrafenib and trametinib can be used in combination to synergistically inhibit ERK activity in BRAFV600E-mutant melanoma cells. The model elucidates molecular mechanisms of vertical inhibition of the BRAFV600E-MEK-ERK cascade and delineates how elevated BRAF concentrations generate drug resistance to dabrafenib and trametinib. The computational simulations further suggest that elevated ATP levels could be a factor in drug resistance to dabrafenib.CONCLUSIONS:
The model can be used to systematically motivate which dabrafenib-trametinib dose combinations, for treating BRAFV600E-mutated melanoma, warrant experimental investigation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Quinasas de Proteína Quinasa Activadas por Mitógenos
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Sistema de Señalización de MAP Quinasas
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Proteínas Proto-Oncogénicas B-raf
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Quinasas MAP Reguladas por Señal Extracelular
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Modelos Biológicos
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Modelos Químicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Br J Cancer
Año:
2021
Tipo del documento:
Article
País de afiliación:
Reino Unido