Simulating BRAFV600E-MEK-ERK signalling dynamics in response to vertical inhibition treatment strategies

Abstract

AbstractIn 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 BRAFV600Einhibitor, and a MEK-inhibitor, are administered in combination. Targeted therapies have been linked to early onsets of drug resistance in clinics, 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-MEKERK 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 parameterized byin vitrodata 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. Moreover, the results demonstrate that whilst DBF monotherapies and DBF-TMT-SCH combination therapies show marked sensitivity to intracellular BRAFV600E concentrationsin silico, TMT and SCH monotherapies do not.