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bioRxiv · 10.1101/2021.04.20.440559

Mathematical modeling quantifies ERK-activity in response to inhibition of the BRAFV600E-MEK-ERK cascade.

Hamis, S.·Kapelyukh, Y.·McLaren, A.·Henderson, C. J.·Wolf, C. R.·Chaplain, M. A. J.
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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 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.

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Hamis, S., Kapelyukh, Y., McLaren, A., Henderson, C. J., Wolf, C. R., Chaplain, M. A. J.. 2021-04-21. Mathematical modeling quantifies ERK-activity in response to inhibition of the BRAFV600E-MEK-ERK cascade.. https://doi.org/10.1101/2021.04.20.440559

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