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Simulating BRAFV600E-MEK-ERK signalling dynamics in response to vertical inhibition treatment strategies
Alice De Carli1, Yury Kapelyukh2, Jochen Kursawe1
1School of Mathematics and Statistics, University of St Andrews, St Andrews, Scotland, UK.
Abstract:
In vertical inhibition treatment strategies, multiple components of an intracellular pathway are simultaneously inhibited. Vertical inhibition of the BRAFV600E-MEK-ERK signalling pathway is a standard of care for treating BRAFV600E-mutated melanoma where two targeted cancer drugs, a BRAFV600E-inhibitor, and a MEK inhibitor, are administered in combination. Targeted therapies have been linked to early onsets of drug resistance, and thus treatment strategies of higher complexities and lower doses have been proposed as alternatives to current clinical strategies. However, finding optimal complex, low-dose treatment strategies is a challenge, as it is possible to design more treatment strategies than are feasibly testable in experimental settings. To quantitatively address this challenge, we develop a mathematical model of BRAFV600E-MEK-ERK signalling dynamics in response to combinations of the BRAFV600E-inhibitor dabrafenib (DBF), the MEK inhibitor trametinib (TMT), and the ERK-inhibitor SCH772984 (SCH). From a model of the BRAFV600E-MEK-ERK pathway, and a set of molecular-level drug-protein interactions, we extract a system of chemical reactions that is parameterised by in vitro data and converted to a system of ordinary differential equations (ODEs) using the law of mass action. The ODEs are solved numerically to produce simulations of how pathway-component concentrations change over time in response to different treatment strategies, i.e., inhibitor combinations and doses. The model can thus be used to limit the search space for effective treatment strategies that target the BRAFV600E-MEK-ERK pathway and warrant further experimental investigation. The results demonstrate that DBF and DBF-TMT-SCH therapies show marked sensitivity to BRAFV600E concentrations in silico, whilst TMT and SCH monotherapies do not.
Insights
Developing a mathematical model helps identify optimal low-dose cancer therapies by simulating BRAFV600E-MEK-ERK pathway inhibition. This approach aids in finding effective drug combinations for melanoma treatment.
Area of Science:
- Oncology
- Systems Biology
- Pharmacology
Background:
- Vertical inhibition targets multiple components of intracellular pathways, like the BRAFV600E-MEK-ERK pathway, for melanoma treatment.
- Targeted therapies, while effective, face challenges with early drug resistance, prompting research into complex, low-dose strategies.
- Designing and testing numerous complex treatment strategies experimentally is often infeasible.
Purpose of the Study:
- To develop a quantitative mathematical model of the BRAFV600E-MEK-ERK signaling pathway.
- To simulate the effects of various drug combinations and doses, including dabrafenib (DBF), trametinib (TMT), and SCH772984 (SCH).
- To reduce the search space for effective treatment strategies and guide experimental investigations.
Main Methods:
- A mathematical model of BRAFV600E-MEK-ERK signaling dynamics was created.
- Drug-protein interactions were translated into a system of chemical reactions.
- Parameterization using in vitro data and conversion to ordinary differential equations (ODEs) via the law of mass action.
- Numerical solution of ODEs to simulate pathway component concentration changes over time under different treatment conditions.
Main Results:
- Simulations explored various inhibitor combinations and doses for the BRAFV600E-MEK-ERK pathway.
- The model demonstrated that dabrafenib (DBF) and triple therapy (DBF-TMT-SCH) exhibited significant sensitivity to BRAFV600E concentrations.
- Trametinib (TMT) and SCH772984 (SCH) monotherapies did not show this sensitivity in silico.
Conclusions:
- The developed mathematical model effectively simulates intracellular signaling pathway dynamics under drug treatment.
- The model serves as a valuable tool for identifying promising, complex, low-dose treatment strategies for BRAFV600E-mutated melanoma.
- In silico results highlight the differential sensitivity of various treatment regimens to BRAFV600E levels, guiding future research.
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