Figure 5.

Combination chemotherapy enriches for clones with increased phenotypic plasticity. Simulations of clones treated with different patterns of combination therapies that include mesenchymal-specific (blue squares) and epithelial-specific treatments (black squares) (see Material and methods). (a–d) Left, the median fold change in clone size during the course of treatment for clones binned by the fraction of their progeny in the epithelial state. Displayed is the median and 90%–10% range of observed medians across 500 simulations. Right, the number of cancer cells surviving at the end of the simulation for each treatment; displayed is the median and 90%–10% range of observed cell numbers across 500 simulations. (a) Combination therapy (orange curve) enriches for clones with increased plasticity, while monotherapies enrich for clones in predominantly one or the other state. Fewer cells survive combination therapy. (b) Increasing the cycles of combination therapies (as shown in (a)) further enriches for clones with increased plasticity. However, resistant populations eventually emerge. The number of cycles of each combination therapy is indicated. (c) Different patterns of combination therapy, with varying proportions of epithelial- and mesenchymal-specific treatments, enrich for different, particular plasticities. (d) More rapid alternation between therapies reduces the enrichment for more plastic clones and more effectively reduces cancer cell numbers. Repeated alternating therapy also prevents the outgrowth of resistant clones, in contrast to repeated sequential therapy. The number of cycles of each therapy is indicated.