Spatial competition constrains resistance to targeted cancer therapy

• Published in: Nature communications 2017-12, Vol.8 (1), p.1995-15, Article 1995
• Main Authors: Bacevic, Katarina, Noble, Robert, Soffar, Ahmed, Wael Ammar, Orchid, Boszonyik, Benjamin, Prieto, Susana, Vincent, Charles, Hochberg, Michael E., Krasinska, Liliana, Fisher, Daniel
• Format: Article
• Language: English
• Subjects: 631/67/1059/2326; 631/80/641; Adaptive control; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Cancer therapies; Cell culture; Cell Culture Techniques; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular Biology; Competition; Cyclin-dependent kinase; Cyclin-dependent kinases; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - genetics; Drug Resistance, Neoplasm - drug effects; Enzyme inhibitors; Female; Fitness; Humanities and Social Sciences; Humans; Kinases; Life Sciences; Mathematical models; Mice; Mice, Nude; Models, Biological; multidisciplinary; Neoplasms - drug therapy; Neoplasms - pathology; Pharmacology; Piperazines - pharmacology; Piperazines - therapeutic use; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Purines - pharmacology; Purines - therapeutic use; Pyridines - pharmacology; Pyridines - therapeutic use; Reproductive fitness; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Spheroids; Spheroids, Cellular - drug effects; Targeted cancer therapy; Therapy; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• 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. Adaptive therapy aims to control tumours by exploiting competition between therapy-sensitive and resistant cells. Here, the authors show that tumour spatial structure is a critical parameter for adaptive therapy as competition for space increases fitness differentials, allowing suppression of resistance with low-dose treatments.