Fibroblasts and alectinib switch the evolutionary games that non-small cell lung cancer plays

Heterogeneity in strategies for survival and proliferation among the cells which constitute a tumour is a driving force behind the evolution of resistance to cancer therapy. The rules mapping the tumour’s strategy distribution to the fitness of individual strategies can be represented as an evolutionary game. We develop a game assay to measure effective evolutionary games in co-culures of alectinib-sensitive and alectinib-resistant non-small cell lung cancer. The games are not only quantitatively different between different environments, but targeted therapy and cancer associated fibroblasts qualitatively switch the type of game being played from Leader to Deadlock. This observation provides the first empirical confirmation of a central theoretical postulate of evolutionary game theory in oncology: we can treat not only the player, but also the game. Although we concentrate on measuring games played by cancer cells, the measurement methodology we develop can be used to advance the study of games in other microscopic systems by providing a quantitative description of non-cell-autonomous effects.