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

Sara Jasmin Hamis*, Yury Kapelyukh, Colin J. Henderson, C. Roland Wolf, Mark Andrew Joseph Chaplain

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

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.

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.

The model can be used to systematically motivate which dabrafenib–trametinib dose combinations, for treating BRAFV600E-mutated melanoma, warrant experimental investigation.
Original languageEnglish
Number of pages9
JournalBritish Journal of Cancer
VolumeFirst Online
Publication statusPublished - 7 Oct 2021


  • Computational science
  • Melanoma
  • Numerical simulations


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