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

## TL;DR

The paper shows how cancer cells adapt their growth to resist drugs, using a model that explains why alternating drug treatments may be more effective.

## Contribution

A novel mathematical model linking phenotypic adaptation to drug resistance in BRAFV600E-mutant melanoma is introduced.

## Key findings

- Phenotypic adaptation is directed toward high-growth states to evade drug effects.
- Intermittent drug treatments may outperform continuous treatments by leveraging phenotypic adaptation.
- A flexible mathematical methodology using ordinary differential equations is proposed for treatment comparison.

## Abstract

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.

Mathematical modelling of phenotypic plasticity reveals directed adaptation toward high-growth states as a possible mechanism underlying differential treatment responses to continuous versus intermittent BRAF inhibition in melanoma in vitro.