Quantifying ERK activity in response to inhibition of the BRAFV600E-MEK-ERK cascade using mathematical modelling

Sara J Hamis,Yury Kapelyukh,C Roland Wolf,Aileen Mclaren,Mark A J Chaplain,Colin J Henderson

doi:10.1038/s41416-021-01565-w

Abstract

BackgroundSimultaneous 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.MethodsWe 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.ResultsThe 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.ConclusionsThe model can be used to systematically motivate which dabrafenib–trametinib dose combinations, for treating BRAFV600E-mutated melanoma, warrant experimental investigation.

Highlights

Simultaneous inhibition of multiple components of the BRAF-MEK-ERK cascade has become a standard of care for treating BRAF-mutant melanoma
Several MAPK kinase kinase (MAPKKK)-MAPK kinase (MAPKK)-Mitogen-activated protein kinase (MAPK) cascades are present in eukaryotic cells, but in this study, we focus our attention on one such cascade: the BRAF-MEK-ERK cascade
We develop a mathematical model that simulates the temporal BRAF-MEKERK signalling dynamics in BRAFV600E-mutant melanoma

Summary

Introduction

Simultaneous inhibition of multiple components of the BRAF-MEK-ERK cascade (vertical inhibition) has become a standard of care for treating BRAF-mutant melanoma. 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. Several MAPKKK-MAPKK-MAPK cascades are present in eukaryotic cells, but in this study, we focus our attention on one such cascade: the BRAF-MEK-ERK cascade Mutations in this signalling pathway have been identified as drivers for tumour development and growth, and this cascade is of particular interest in the treatment of cancer. These phosphorylation events, which are controlled by both the amplitude and the duration of ERK activation, are crucial in regulating intracellular processes, including cell proliferation

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