Spatial competition constrains resistance to targeted cancer therapy

Katarina Bacevic (1) , Robert Noble (2) , Ahmed Soffar (1) , Orchid Wael Ammar (1) , Benjamin Boszonyik (1) , Susana Prieto (1) , Charles Vincent (3) , Michael E Hochberg (2, 4) , Liliana Krasinska (1) , Daniel Fisher (1)

1 IGMM - Institut de Génétique Moléculaire de Montpellier
2 UMR ISEM - Institut des Sciences de l'Evolution de Montpellier
3 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
4 Santa Fe Institute

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.

Domaines: Cancer; Biologie cellulaire

Katarina Bacevic, Robert Noble, Ahmed Soffar, Orchid Wael Ammar, Benjamin Boszonyik, et al.. Spatial competition constrains resistance to targeted cancer therapy. Nature Communications, 2017, 8, pp.1995. ⟨10.1038/s41467-017-01516-1⟩. ⟨hal-02120922⟩