Spatial competition constrains resistance to targeted cancer therapy.

ABSTRACT: Adaptive therapy (AT) aims to control tumour burden by maintaining therapy-sensitive cells to exploit their competition with resistant cells. This relies on the assumption that resistant cells have impaired cellular fitness. Here, using a model of resistance to a pharmacological cyclin-dependent kinase inhibitor (CDKi), we show that this assumption is valid when competition between cells is spatially structured. We generate CDKi-resistant cancer cells and find that they have reduced proliferative fitness and stably rewired cell cycle control pathways. Low-dose CDKi outperforms high-dose CDKi in controlling tumour burden and resistance in tumour spheroids, but not in monolayer culture. Mathematical modelling indicates that tumour spatial structure amplifies the fitness penalty of resistant

SUBMITTER: Bacevic K 

PROVIDER: S-EPMC5722825 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature