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.

A modified fluctuation-test framework characterizes the population dynamics and mutation rate of colorectal cancer persister cells / M. Russo, S. Pompei, A. Sogari, M. Corigliano, G. Crisafulli, A. Puliafito, S. Lamba, J. Erriquez, A. Bertotti, M. Gherardi, F. Di Nicolantonio, A. Bardelli, M. Cosentino Lagomarsino. - In: NATURE GENETICS. - ISSN 1546-1718. - 54:7(2022), pp. 976-984. [10.1038/s41588-022-01105-z]

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

M. Gherardi;M. Cosentino Lagomarsino
Ultimo
2022

Abstract

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.
Humans; Population Dynamics; Colorectal Neoplasms; Mutation Rate
Settore FIS/02 - Fisica Teorica, Modelli e Metodi Matematici
Settore BIO/18 - Genetica
Settore MED/06 - Oncologia Medica
Settore MED/03 - Genetica Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/946328
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