title: 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 wild-type mice triggered synergistic gastrointestinal toxicities (GIT) that were associated with the death of Lgr5(+) crypt base columnar 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 affecting 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.
authors.affiliation: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Departmental of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Division of Hematology/Oncology, Penn State Hershey Cancer Institute, Hershey, Pennsylvania.
authors.forename: Niklas K
authors.initials: NK
authors.lastname: Finnberg
authors.affiliation: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Departmental of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Division of Hematology/Oncology, Penn State Hershey Cancer Institute, Hershey, Pennsylvania.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Gokare
authors.affiliation: Division of Hematology/Oncology, Penn State Hershey Cancer Institute, Hershey, Pennsylvania.
authors.forename: Arunasalam
authors.initials: A
authors.lastname: Navaraj
authors.affiliation: Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Infections/National Cancer Institute, Bethesda, Maryland.
authors.forename: Krystle A
authors.initials: KA
authors.lastname: Lang Kuhs
authors.affiliation: Department of Radiation Oncology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: George
authors.initials: G
authors.lastname: Cerniglia
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Cognitive Brain Sciences, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Motoyama
authors.affiliation: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Departmental of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Division of Hematology/Oncology, Penn State Hershey Cancer Institute, Hershey, Pennsylvania. wafik.eldeiry@gmail.com.
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand