Figure 6.

Drug-induced and drug-free population dynamics are explained as re-equilibrations over epigenetic landscapes. (A) Schematic representation of a drug-addition and drug-removal cycle for a cancer cell population: (top left) cells begin in complete growth medium and are in a dynamic equilibrium across basins of a drug-free epigenetic landscape; (top left to bottom left) exposure to a drug modifies the landscape, taking the system out of equilibrium; (bottom left to bottom right) the population re-equilibrates over the new drug-induced landscape by reducing cell proportions in the regressing (R) and expanding (E) basins and increasing the proportion in the stationary (S) basin; (bottom right) the idling state corresponds to the newly achieved dynamic equilibrium; (bottom right to top right) removal of the drug reestablishes the drug-free epigenetic landscape and, again, takes the system out of equilibrium; (top right to top left) the population re-equilibrates over the drug-free landscape, returning the system to the original dynamic equilibrium. Arrow thicknesses represent relative transition rates at each stage of the re-equilibration process. (B) Clonal (top) and parental (bottom) drug-response population dynamics illustrating the connection to the different stages of the drug-induced re-equilibration process. Numbers and colors (orange, regressing; green, stationary; blue, expanding) correspond to those in the schematic above. To see this figure in color, go online.