Unknown

Dataset Information

0

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


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.

SUBMITTER: Hamis SJ 

PROVIDER: S-EPMC8608797 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC7393480 | biostudies-literature
| S-EPMC5560871 | biostudies-literature
| S-EPMC5096947 | biostudies-literature
| S-EPMC9497977 | biostudies-literature
| S-EPMC5882509 | biostudies-literature
| S-EPMC5704016 | biostudies-literature
| S-EPMC7476408 | biostudies-literature
| S-EPMC4481642 | biostudies-literature
| S-EPMC4910922 | biostudies-literature
| S-EPMC6106940 | biostudies-literature