A modified fluctuation-test framework characterizes the population dynamics and mutation rate of colorectal cancer persister cells
Mariangela Russo, Simone Pompei, Alberto Sogari, Mattia Corigliano, Giovanni Crisafulli, Alberto Puliafito, Simona Lamba, Jessica Erriquez, Andrea Bertotti, Marco Gherardi, Federica Di Nicolantonio, Alberto Bardelli, Marco Cosentino Lagomarsino
Abstract
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.