Growth rate-driven modelling suggests that phenotypic adaptation drives drug resistance in BRAFV600E-mutant melanoma

Journal article

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 informed by growth-rate data of WM239A-BRAFV600E cells challenged with the BRAF-inhibitor encorafenib. We use an individual-based model (IBM) in which each cell is 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. To describe how cells transition between phenotype states, we explore a gamut of candidate models common in the mathematical biology literature. Comparing these on their ability to reproduce in vitro growth curves, data-matched simulations suggest that phenotypic adaptation is directed towards states of high net growth rates, enabling the evasion of drug-effects. The model subsequently provides an explanation for when and why intermittent treatments outperform continuous treatments in the studied system, and demonstrates the benefits of not only targeting, but also leveraging, phenotypic adaptation in treatment protocols. Building on the IBM, we present a flexible mathematical methodology based on ordinary differential equations to compare responses to continuous and intermittent treatments through long-term effective net growth rates.

Authors: Hamis, S; Browning, AP; Jenner, AL; Villa, C; Maini, PK

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Communications Biology
• Publication date: 2026-02-26
• Acceptance date: 2026-02-17
• DOI: 10.1038/s42003-026-09760-2
• EISSN: 2399-3642
• ISSN: 2399-3642
• Language: English
• Keywords: Adaptation (eye); Gene; Drug; Phenotype; Drug resistance; Melanoma; Phenotypic plasticity; Phenotypic switching