A modified fluctuation-test framework characterizes population dynamics and mutation rate of cancer persister cells

Compelling evidence shows that cancer persister cells represent a major limit to the long-term efficacy of targeted therapies. However, the phenotype and population dynamics of cancer persister cells remain unclear. We developed a quantitative framework to study persisters by combining experimental characterization and mathematical modeling. We found that, in colorectal cancer, a fraction of persisters slowly replicate. Clinically approved targeted therapies induce a switch to drug tolerant persisters and a temporary 7- to 50-fold increase of their mutation rate, thus increasing the number of persisters-derived resistant cells. These findings reveal that treatment may influence persistence and mutability in cancer cells and pinpoints new therapeutic targets to restrict tumor recurrence