City Research Online

Spatial competition constrains resistance to targeted cancer therapy

Bacevic, K., Noble, R. ORCID: 0000-0002-8057-4252, Soffar, A. , Ammar, O. W., Boszonyik, B., Prieto, S., Vincent, C., Hochberg, M. E., Krasinska, L. & Fisher, D. (2017). Spatial competition constrains resistance to targeted cancer therapy. Nature Communications, 8, 1995. doi: 10.1038/s41467-017-01516-1


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 cells, and identifies their relative fitness as a critical determinant of the clinical benefit of AT. Our results justify further investigation of AT with kinase inhibitors.

Publication Type: Article
Subjects: Q Science > QA Mathematics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Departments: School of Science & Technology > Mathematics
Text - Published Version
Available under License Creative Commons: Attribution International Public License 4.0.

Download (1MB) | Preview



Downloads per month over past year

View more statistics

Actions (login required)

Admin Login Admin Login