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.

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

Russo, Mariangela;Sogari, Alberto;Crisafulli, Giovanni;Puliafito, Alberto;Bertotti, Andrea;Di Nicolantonio, Federica;Bardelli, Alberto;
2022

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.
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Russo, Mariangela; Pompei, Simone; Sogari, Alberto; Corigliano, Mattia; Crisafulli, Giovanni; Puliafito, Alberto; Lamba, Simona; Erriquez, Jessica; Bertotti, Andrea; Gherardi, Marco; Di Nicolantonio, Federica; Bardelli, Alberto; Cosentino Lagomarsino, Marco
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1869137
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