Tolerance to colibactin correlates with homologous recombination proficiency and resistance to irinotecan in colorectal cancer cells
Alberto Sogari, Emanuele Rovera, Gaia Grasso, Elisa Mariella, Nicole M. Reilly, Simona Lamba, Gianluca Mauri, Erika Durinikova, Pietro Paolo Vitiello, Annalisa Lorenzato, Marco Avolio, Eleonora Piumatti, Emanuela Bonoldi, Maria Costanza Aquilano, Sabrina Arena, Andrea Sartore‐Bianchi, Salvatore Siena, Livio Trusolino, Manuela Donalisio, Mariangela Russo, Federica Di Nicolantonio, David Lembo, Alberto Bardelli
Abstract
The bacterial genotoxin colibactin promotes colorectal cancer (CRC) tumorigenesis, but systematic assessment of its impact on DNA repair is lacking, and its effect on response to DNA-damaging chemotherapeutics is unknown. We find that CRC cell lines display differential response to colibactin on the basis of homologous recombination (HR) proficiency. Sensitivity to colibactin is induced by inhibition of ATM, which regulates DNA double-strand break repair, and blunted by HR reconstitution. Conversely, CRC cells chronically infected with colibactin develop a tolerant phenotype characterized by restored HR activity. Notably, sensitivity to colibactin correlates with response to irinotecan active metabolite SN38, in both cell lines and patient-derived organoids. Moreover, CRC cells that acquire colibactin tolerance develop cross-resistance to SN38, and a trend toward poorer response to irinotecan is observed in a retrospective cohort of CRCs harboring colibactin genomic island. Our results shed insight into colibactin activity and provide translational evidence on its chemoresistance-promoting role in CRC.