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

A modified fluctuation test applied to colorectal cancer cells shows that EGFR/BRAF inhibitor-induced persisters slowly proliferate and have an increased mutation rate. Error-prone DNA polymerases are identified as potential targets to avoid tumor recurrence following treatment with these drugs. 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 replicates. 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 persister-derived resistant cells. These findings reveal that treatment may influence persistence and mutability in cancer cells and pinpoint inhibition of error-prone DNA polymerases as a strategy to restrict tumor recurrence.