Agonists of the TRAIL Death Receptor DR5 Sensitize Intestinal Stem Cells to Chemotherapy-Induced Cell Death and Trigger Gastrointestinal Toxicity

Abstract

The combination of TRAIL death receptor agonists and radiochemotherapy to treat advanced cancers continues to be investigated in clinical trials. We previously showed that normal cells with a functional DNA damage response (DDR) upregulate the expression of death inducing receptor DR5/TRAILR2/TNFRSF10B in a p53-dependent manner that sensitizes them to treatment with DR5 agonists. However, it is unclear if targeting DR5 selectively sensitizes cancer cells to agonist treatment following exposure to DNA-damaging chemotherapy, and to what extent normal tissues are targeted. Here, we show that the combined administration of the DR5 agonistic monoclonal antibody (mAb) and chemotherapy to wildtype mice triggered synergistic gastrointestinal toxicities (GIT) that were associated with the death of Lgr5+ crypt base columnar (CBC) stem cells in a p53- and DR5-dependent manner. Furthermore, we confirmed that normal human epithelial cells treated with the human DR5-agonistic mAb and chemotherapeutic agents were also greatly sensitized to cell death. Interestingly, our data also indicated that genetic or pharmacologic targeting of Chk2 may counteract GIT without negatively impacting the antitumor responses of combined DR5 agonist/chemotherapy treatment, further linking the DDR to TRAIL death receptor signaling in normal cells. In conclusion, the combination of DR5-targeting agonistic mAbs with DNA damaging chemotherapy may pose a risk of developing toxicity-induced conditions, and the effects of mAb-based strategies on the dose-limiting toxicity of chemotherapy must be considered when establishing new combination therapies.

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“…Moreover, DR agonists activate apoptosis independently of p53 status, providing another rationale for using DR agonists in combination with other therapeutic agents to overcome resistance to cell death [157]. Various chemotherapeutic drugs have been found in preclinical models to synergize with DR agonists, including 5FU [48,158,159], gemcitabine [160,161], irinotecan [159,162], Adriamycin [163], and paclitaxel [163]. The proposed mechanisms to sensitize cells to TRAIL include enhanced DISC formation, and up- or down-regulation of pro- or anti-apoptotic regulators.…”