Abstract 2926: DR5-targeting sensitizes Lgr5+ stem cells to p53 and Chk2-dependent chemotherapy-induced cell death and produces dose-limiting gastrointestinal toxicity (GIT)

Abstract

Abstract Current ongoing clinical trials are exploring combined targeting of the TRAIL-death receptor DR5 with radiochemotherapy. It is not clear mechanistically why targeting of the DR5 increasingly sensitizes cancer cells to cell death without affecting cells in normal tissues. Preclinical data suggests that integration of DR5 agonist antibodies into chemotherapy protocols has the promise to significantly improve cancer specific responses without negatively impacting dose-limiting toxicities. Here we show that targeting of DR5 in mice with the mouse-specific mAb MD5-1 in combination with chemotherapy triggers synergistic gastrointestinal toxicities (GIT) that is associated with the death of Lgr5+ crypt basal columnar (CBC) cells. This type of GIT is mediated by p53 and in the case of irinotecan, the cell cycle checkpoint kinase 2 (Chk2). Pharmacologic targeting of Chk2 sensitized syngeneic mouse colorectal cancer tumors lacking P53 to the irinotecan/MD5-1 combination while at the same time protecting the gastrointestinal tract from injury. Our data indicates that blockade of cell cycle checkpoint kinases can help prevent GIT triggered by a combination of DNA damaging chemotherapy and DR5 agonists. Pharmacologic targeting of Chk2 can improve the anti-tumor response of such drug combinations and subsequently provides a rationale on how to improve therapeutic indices of DR5-targeting in the context of chemotherapy usage. Citation Format: Niklas K. Finnberg, Prashanth Gokare, Arunasalam Navaraj, Krystle A. Lang Kuhs, George Cerniglia, Hideo Yagita, Kazuyoshi Takeda, Noboru Motoyama, Wafik S. El-Deiry. DR5-targeting sensitizes Lgr5+ stem cells to p53 and Chk2-dependent chemotherapy-induced cell death and produces dose-limiting gastrointestinal toxicity (GIT). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2926. doi:10.1158/1538-7445.AM2015-2926