The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease.

The development of de novo resistance is a major disadvantage in molecularly targeted therapies. While much focus is on cell-intrinsic mechanisms, the microenvironment is also known to play a crucial role. This study examines interactions between cancer cells and cancer associated fibroblasts (CAFs) to understand the local crosstalk facilitating residual disease. Using a hybrid-discrete-continuum model, we explore how treatment-induced stress responses can elicit CAF activation and how breaks in treatment allow microenvironment normalisation. We investigate how fluctuating environmental conditions shape the local crosstalk and ultimately drive residual disease. Our experimentally calibrated model identifies environmental and treatment conditions that allow tumour eradication and those that enable survival. We find two distinct mechanisms that underpin residual disease: vasculature-limited drug delivery and CAF-mediated rescue. This work provides a better understanding of the mechanisms that drive the creation of localised residual disease, crucial to informing the development of more effective treatment protocols.