Tsuyoshi Takashima1,2, Daiki Taniyama1, Naoya Sakamoto3, Maika Yasumoto1, Ryuichi Asai1, Takuya Hattori1, Ririno Honma1, Pham Quoc Thang1, Shoichi Ukai1, Ryota Maruyama1, Kenji Harada1, Kazuya Kuraoka4,5, Kazuaki Tanabe6, Atsuo T Sasaki7,8, Hideki Ohdan6, Eiichi Morii2, Junko Murai9, Wataru Yasui1. 1. Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. 2. Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan. 3. Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. naosakam@east.ncc.go.jp. 4. Institute for Clinical Research, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan. 5. Department of Diagnostic Pathology, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan. 6. Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. 7. Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA. 8. Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan. 9. Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan. muraij@ttck.keio.ac.jp.
Abstract
BACKGROUND: Although unresectable or recurrent gastric cancers (GC) are frequently treated with platinum-based chemotherapy, response to treatment remains unpredictable. Because Schlafen 11 (SLFN11) is recently identified as a critical determinant of platinum sensitivity, we investigated the potential clinical utility of SLFN11 in the treatment of GC. METHODS: We analysed the correlation between SLFN11 expression and overall survival in 169 GC patients by our established immunohistochemical approach. The impact of SLFN11 expression on the response to platinum and transition of SLFN11 expression upon long-term treatment with platinum were examined using GC cell lines and organoids. RESULTS: GC patients with high-SLFN11 expression exhibited significantly better survival than those with low-SLFN11 expression, and the significance increased when we selected patients treated with platinum-based chemotherapy. Knockout of SLFN11 and reactivation of SLFN11 in GC cells conferred resistance and sensitivity to platinum, respectively. In GC cells and organoids, long-term treatment with oxaliplatin suppressed SLFN11 expression while imparting drug resistance. The acquired resistance to oxaliplatin was reversed by reactivation of SLFN11 with epigenetic modifying drugs. CONCLUSIONS: This is the first report revealing definitive clinical implications of SLFN11 in the treatment of GC patients and providing novel strategies for the drug selection based on SLFN11 expression.
BACKGROUND: Although unresectable or recurrent gastric cancers (GC) are frequently treated with platinum-based chemotherapy, response to treatment remains unpredictable. Because Schlafen 11 (SLFN11) is recently identified as a critical determinant of platinum sensitivity, we investigated the potential clinical utility of SLFN11 in the treatment of GC. METHODS: We analysed the correlation between SLFN11 expression and overall survival in 169 GC patients by our established immunohistochemical approach. The impact of SLFN11 expression on the response to platinum and transition of SLFN11 expression upon long-term treatment with platinum were examined using GC cell lines and organoids. RESULTS: GC patients with high-SLFN11 expression exhibited significantly better survival than those with low-SLFN11 expression, and the significance increased when we selected patients treated with platinum-based chemotherapy. Knockout of SLFN11 and reactivation of SLFN11 in GC cells conferred resistance and sensitivity to platinum, respectively. In GC cells and organoids, long-term treatment with oxaliplatin suppressed SLFN11 expression while imparting drug resistance. The acquired resistance to oxaliplatin was reversed by reactivation of SLFN11 with epigenetic modifying drugs. CONCLUSIONS: This is the first report revealing definitive clinical implications of SLFN11 in the treatment of GC patients and providing novel strategies for the drug selection based on SLFN11 expression.
Authors: Ahmed Adham Raafat Elsayed; Sarmad Al-Marsoummi; Emilie E Vomhof-Dekrey; Marc D Basson Journal: Cancer Genomics Proteomics Date: 2022 May-Jun Impact factor: 4.069
Authors: Bingnan Zhang; Kavya Ramkumar; Robert John Cardnell; Carl Michael Gay; C Allison Stewart; Wei-Lien Wang; Junya Fujimoto; Ignacio I Wistuba; Lauren Averett Byers Journal: Br J Cancer Date: 2021-07-22 Impact factor: 9.075