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

Abstract

AbstractBackgroundSimultaneous 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 upon a system of chemical reactions that describes cascade signalling dynamics. Using mass action kinetics, the chemical reactions are re-expressed as ordinary differential equations which 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.