A modified fluctuation-test framework characterizes the population dynamics and mutation rate of colorectal 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...

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Bibliographic Details
Published in:Nature genetics Vol. 54; no. 7; pp. 976 - 984
Main Authors: 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
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.07.2022
Nature Publishing Group
Subjects:
631/208
631/67/1504/1885
639/705
Agriculture
Animal Genetics and Genomics
Anti-Bacterial Agents - pharmacology
Apoptosis
Biomedical and Life Sciences
Biomedicine
Cancer
Cancer Research
Cell cycle
Cell division
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
DNA polymerase
DNA-directed DNA polymerase
Drug dosages
Gene Function
Genotype & phenotype
Human Genetics
Humans
Mathematical models
Microscopy
Mutation
Mutation Rate
Mutation rates
Phenotypes
Population
Population Dynamics
Tumors
ISSN:1061-4036, 1546-1718, 1546-1718
Online Access:Get full text
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Summary: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 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.
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ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-022-01105-z