The utility of Schlafen 11 (SLFN11) expression as a predictive biomarker for platinum-based chemotherapy has been established for cancers from different histologies. However, the therapeutic relevance of SLFN11 in bladder cancer (BC) is unknown. Here, we examined the clinicopathological significance of SLFN11 expression across 120 BC cases by immunohistochemistry. We divided them into two cohorts, one including 50 patients who received adjuvant or neoadjuvant platinum-based chemotherapy, and the other including 70 BC patients treated by surgical resection without chemotherapy. In the cohort of 50 BC cases treated with platinum-based chemotherapy, the SLFN11-positive group (N = 25) showed significantly better overall survival than the SLFN11-negative group (N = 25, P = 0.012). SLFN11 expression correlated significantly with the expression of luminal subtype marker GATA3. Multivariate analyses identified SLFN11 expression as an independent prognostic predictor (OR, 0.32; CI, 0.11-0.91; P = 0.033). Conversely, in the cohort of 70 BC cases not receiving platinum-based chemotherapy, the SLFN11-positive group (N = 29) showed significantly worse overall survival than the SLFN11-negative group (N = 41, P = 0.034). In vitro analyses using multiple BC cell lines confirmed that knocking-out of SLFN11 rendered cells resistant to cisplatin. The epigenetic modifying drugs 5-azacytidine and entinostat restored SLFN11 expression and re-sensitized cells to cisplatin and carboplatin in SLFN11-negative BC cell lines. We conclude that SLFN11 is a predictive biomarker for BC patients who undergo platinum-based chemotherapy and that the combination of epigenetic modifiers could rescue refractory BC patients to platinum derivatives by reactivating SLFN11 expression.
Cancer science. 2021 Nov 22 [Epub ahead of print]
Daiki Taniyama, Naoya Sakamoto, Tsuyoshi Takashima, Masahiko Takeda, Quoc Thang Pham, Shoichi Ukai, Ryota Maruyama, Kenji Harada, Takashi Babasaki, Yohei Sekino, Tetsutaro Hayashi, Kazuhiro Sentani, Yves Pommier, Junko Murai, Wataru Yasui
Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Department of Urology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan., Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA., Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.