Growth rate-driven modelling reveals how phenotypic adaptation drives drug resistance in BRAFV600E-mutant melanoma - Archive ouverte HAL
Pré-Publication, Document De Travail Année : 2024

Growth rate-driven modelling reveals how phenotypic adaptation drives drug resistance in BRAFV600E-mutant melanoma

Résumé

Phenotypic adaptation, the ability of cells to change phenotype in response to external pressures, has been identified as a driver of drug resistance in cancer. To quantify phenotypic adaptation in BRAFV600E-mutant melanoma, we develop a theoretical model that emerges from data analysis of WM239A-BRAFV600E cell growth rates in response to drug challenge with the BRAF-inhibitor encorafenib. Our model constitutes a cell population model in which each cell is individually described by one of multiple discrete and plastic phenotype states that are directly linked to drug-dependent net growth rates and, by extension, drug resistance. Data-matched simulations reveal that phenotypic adaptation in the cells is directed towards states of high net growth rates, which enables evasion of drug-effects. The model subsequently provides an explanation for when and why intermittent treatments outperform continuous treatments in vitro, and demonstrates the benefits of not only targeting, but also leveraging, phenotypic adaptation in treatment protocols.
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Dates et versions

hal-04851795 , version 1 (20-12-2024)

Identifiants

  • HAL Id : hal-04851795 , version 1

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Sara Hamis, Alexander P Browning, Adrianne L Jenner, Chiara Villa, Philip K Maini, et al.. Growth rate-driven modelling reveals how phenotypic adaptation drives drug resistance in BRAFV600E-mutant melanoma. 2024. ⟨hal-04851795⟩
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