Tolerance to colibactin correlates with homologous recombination proficiency and resistance to irinotecan in colorectal cancer cells.

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.
Competing Interests: Declaration of interests The authors declare the following competing interests, which are unrelated to the results of the study. A.B. reports receiving commercial research grants from Neophore, AstraZeneca, and Boehringer; he is an advisory board member/unpaid consultant for Inivata and Neophore, holds ownership interest in Neophore, and is an advisory board member/consultant for Illumina, Guardant Health, Inivata, and Roche/Genentech Global CRC. F.D.N. received honoraria from Pierre Fabre. L.T. has received research grants from Menarini, Merck KGaA, Merus, Pfizer, Servier, and Symphogen. S.A. acted as consultant for MSD Italia outside the submitted work and has a patent (102022000007535) pending. A.S.-B. is an advisory board member for Amgen, Bayer, Novartis, Pierre Fabre, and Servier. S.S. is an advisory board member for Agenus, AstraZeneca, Bayer, Bristol Myers Squibb, CheckmAb, Daiichi Sankyo, Guardant Health, Menarini, Merck, Novartis, Roche-Genentech, and Seagen.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)