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

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De Carli, AliceUniv St Andrews, Sch Math & Stat, St Andrews, Scotland. (författare)

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

Artikel/kapitelEngelska2024

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Springer Nature,2024
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LIBRIS-ID:oai:DiVA.org:uu-530582
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-530582URI
https://doi.org/10.1038/s41540-024-00379-9DOI

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Språk:engelska
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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.

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Kapelyukh, YuryUniv Dundee, Ninewells Hosp, Jacqui Wood Canc Ctr, Sch Med, Dundee, Scotland.;Univ Dundee, Med Sch, Dundee, Scotland. (författare)
Kursawe, JochenUniv St Andrews, Sch Math & Stat, St Andrews, Scotland. (författare)
Chaplain, Mark A. J.Univ St Andrews, Sch Math & Stat, St Andrews, Scotland. (författare)
Wolf, C. RolandUniv Dundee, Ninewells Hosp, Jacqui Wood Canc Ctr, Sch Med, Dundee, Scotland.;Univ Dundee, Med Sch, Dundee, Scotland. (författare)
Hamis, SaraUppsala universitet,Avdelningen för systemteknik,Univ St Andrews, Sch Math & Stat, St Andrews, Scotland.;Tampere Univ, Fac Med & Hlth Technol, Tampere Inst Adv Study, Tampere, Finland.(Swepub:uu)sarha467 (författare)
Univ St Andrews, Sch Math & Stat, St Andrews, Scotland.Univ Dundee, Ninewells Hosp, Jacqui Wood Canc Ctr, Sch Med, Dundee, Scotland.;Univ Dundee, Med Sch, Dundee, Scotland. (creator_code:org_t)

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Ingår i:npj systems biology and applications.: Springer Nature10:12056-7189

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Av författaren/redakt...: De Carli, Alice; Kapelyukh, Yury; Kursawe, Jochen; Chaplain, Mark A ...; Wolf, C. Roland; Hamis, Sara

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Farmakologi och ...

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Av lärosätet: Uppsala universitet

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