Functional mismatch repair and inactive p53 drive sensitization of colorectal cancer cells to irinotecan via the IAP antagonist BV6

Abstract

A common strategy to overcome acquired chemotherapy resistance is the combination of a specific anticancer drug (e.g., topoisomerase I inhibitor irinotecan) together with a putative sensitizer. The purpose of this study was to analyze the cytostatic/cytotoxic response of colorectal carcinoma (CRC) cells to irinotecan, depending on the mismatch repair (MMR) and p53 status and to examine the impact of BV6, a bivalent antagonist of inhibitors of apoptosis c-IAP1/c-IAP2, alone or combined with irinotecan. Therefore, several MSH2- or MSH6-deficient cell lines were complemented for MMR deficiency, or MSH6 was knocked out/down in MMR-proficient cells. Upon irinotecan, MMR-deficient/p53-mutated lines repaired DNA double-strand breaks by homologous recombination less efficiently than MMR-proficient/p53-mutated lines and underwent elevated caspase-9-dependent apoptosis. Opposite, BV6-mediated sensitization was achieved only in MMR-proficient/p53-mutated cells. In those cells, c-IAP1 and c-IAP2 were effectively degraded by BV6, caspase-8 was fully activated, and both canonical and non-canonical NF-κB signaling were triggered. The results were confirmed ex vivo in tumor organoids from CRC patients. Therefore, the particular MMR+/p53mt signature, often found in non-metastasizing (stage II) CRC might be used as a prognostic factor for an adjuvant therapy using low-dose irinotecan combined with a bivalent IAP antagonist.

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Acknowledgements

We thank Anna Frumkina for conducting neutral comet assay. The work was financed by Dr. Mildred Scheel Stiftung für Krebsforschung to MTT.

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MTT: study design, experimental work, data analysis, paper writing. CS: experimental work. BR: technical assistance, experimental work. AB: contribution to a new model/methodology. MC: discussion and consulting.

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Correspondence to Maja T. Tomicic.

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Tomicic, M.T., Steigerwald, C., Rasenberger, B. et al. Functional mismatch repair and inactive p53 drive sensitization of colorectal cancer cells to irinotecan via the IAP antagonist BV6. Arch Toxicol 93, 2265–2277 (2019). https://doi.org/10.1007/s00204-019-02513-7

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Keywords

  • IAP antagonist
  • Irinotecan
  • Colorectal cancer
  • Mismatch repair
  • p53
  • NF-κB