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;
2022-01-01

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.
2022
1
26
Russo, Mariangela; Pompei, Simone; Sogari, Alberto; Corigliano, Mattia; Crisafulli, Giovanni; Puliafito, Alberto; Lamba, Simona; Erriquez, Jessica; Be...espandi
File in questo prodotto:
File Dimensione Formato  
BARDELLI_NG-A57462R3_Edver_1650648800_1.pdf

Accesso aperto

Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 570.54 kB
Formato Adobe PDF
570.54 kB Adobe PDF Visualizza/Apri
Russo et al_Nat Gen 2022_compressed.pdf

Accesso aperto

Tipo di file: PDF EDITORIALE
Dimensione 2.97 MB
Formato Adobe PDF
2.97 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1869137
Citazioni
  • ???jsp.display-item.citation.pmc??? 16
  • Scopus 21
  • ???jsp.display-item.citation.isi??? 22
social impact