Related Experiment Video

Updated: Oct 17, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

6.2K

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

Sara J Hamis1, Yury Kapelyukh2, Aileen McLaren2

  • 1School of Mathematics and Statistics, University of St Andrews, St Andrews, Scotland, UK. sjh37@st-andrews.ac.uk.

British Journal of Cancer
|October 8, 2021
PubMed
Abstract

Insights

Vertical inhibition with dabrafenib and trametinib synergistically suppresses BRAF-mutant melanoma cell proliferation. This mathematical model elucidates mechanisms and identifies elevated BRAF and ATP as potential resistance factors.

Area of Science:

  • Molecular Biology
  • Cancer Signaling Pathways
  • Mathematical Modeling

Background:

  • Vertical inhibition of the BRAF-MEK-ERK pathway is standard for BRAF-mutant melanoma.
  • The precise molecular mechanisms of synergistic ERK suppression remain unclear.

Purpose of the Study:

  • To develop a mathematical model of the BRAFV600E-MEK-ERK cascade.
  • To elucidate the synergistic effects of dabrafenib and trametinib on ERK activity.
  • To identify mechanisms of drug resistance.

Main Methods:

  • Developed a mechanistic mathematical model of BRAFV600E-MEK-ERK signaling.
  • Used mass action kinetics and ordinary differential equations.
  • Parameterized the model with in vitro data and solved numerically.

Main Results:

  • Quantified synergistic ERK inhibition by dabrafenib and trametinib in BRAFV600E melanoma.
  • Elucidated molecular mechanisms of vertical inhibition.
  • Identified elevated BRAF and ATP as potential drivers of drug resistance.

Conclusions:

  • The model guides optimal dabrafenib-trametinib dosing strategies for BRAFV600E melanoma.
  • Provides a framework for understanding and overcoming drug resistance.

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