Tolerance to colibactin correlates with homologous recombination proficiency and resistance to irinotecan in colorectal cancer cells
Sogari, A. et al. (2024) Tolerance to colibactin correlates with homologous recombination proficiency and resistance to irinotecan in colorectal cancer cells. Cell Rep Med. 15:101376. DOI:10.1016/j.xcrm.2023.101376.
This study investigates the relationship between tolerance to colibactin, a bacterial genotoxin, and homologous recombination (HR) proficiency in colorectal cancer (CRC) cells. The researchers demonstrate that CRC cell lines exhibit differential responses to colibactin based on their HR status. Cells proficient in HR show tolerance to colibactin-induced DNA damage, whereas HR-deficient cells are sensitive to this genotoxin. Chronic exposure to colibactin in HR-deficient cells leads to the selection of HR-proficient cells that develop resistance to the chemotherapeutic drug irinotecan. This study highlights the potential of colibactin to drive CRC evolution towards DNA repair proficiency, impacting treatment outcomes with irinotecan. Furthermore, patient-derived organoids (PDOs) with differing sensitivities to irinotecan were also tested, revealing a correlation between colibactin sensitivity and irinotecan resistance, providing translational relevance to the findings.
Keywords: Colibactin, homologous recombination, DNA damage repair, irinotecan resistance, colorectal cancer, patient-derived organoids, bacterial genotoxin, chemotherapy resistance
