The development of drug resistance in metastatic tumours under chemotherapy: an evolutionary perspective

TL;DR

This paper develops a mathematical model to study how metastatic tumors evolve resistance to chemotherapy, highlighting factors like cell migration, drug delivery, and tumor environment, with implications for treatment strategies.

Contribution

It introduces a coupled PDE and pharmacokinetic model for metastatic tumor evolution under chemotherapy, calibrated for BRAF-mutated melanoma, and analyzes resistance development through simulations.

Findings

Chemotherapy may promote metastatic spread.

Metastatic sites are less affected by chemotherapy.

Cell migration influences resistance development.

Abstract

We present a mathematical model of the evolutionary dynamics of a metastatic tumour under chemotherapy, comprising non-local partial differential equations for the phenotype-structured cell populations in the primary tumour and its metastasis. These equations are coupled with a physiologically-based pharmacokinetic model of drug delivery, implementing a realistic delivery schedule. The model is carefully calibrated from the literature, focusing on BRAF-mutated melanoma treated with Dabrafenib as a case study. By means of long-time asymptotic analysis, global sensitivity analysis and numerical simulations, we explore the impact of cell migration from the primary to the metastatic site, physiological aspects of the tumour sites and drug dose on the development of drug resistance and treatment efficacy. Our findings provide a possible explanation for empirical evidence indicating that chemotherapy may foster metastatic spread and that metastatic sites may be less impacted by chemotherapy.