1. Prognostic impact of Schlafen 11 in bladder cancer patients treated with platinum-based chemotherapy.
- Author
-
Taniyama D, Sakamoto N, Takashima T, Takeda M, Pham QT, Ukai S, Maruyama R, Harada K, Babasaki T, Sekino Y, Hayashi T, Sentani K, Pommier Y, Murai J, and Yasui W
- Subjects
- Aged, Antineoplastic Agents pharmacology, Azacitidine pharmacology, Benzamides pharmacology, Biomarkers, Tumor metabolism, Cell Line, Tumor, Chemotherapy, Adjuvant, Cisplatin pharmacology, Cisplatin therapeutic use, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Drug Synergism, Female, GATA3 Transcription Factor metabolism, Humans, Male, Nuclear Proteins genetics, Platinum pharmacology, Prognosis, Pyridines pharmacology, Urinary Bladder Neoplasms metabolism, Urinary Bladder Neoplasms mortality, Urinary Bladder Neoplasms surgery, Antineoplastic Agents therapeutic use, Nuclear Proteins metabolism, Platinum therapeutic use, Urinary Bladder Neoplasms drug therapy
- Abstract
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 clinicopathologic significance of SLFN11 expression across 120 BC cases by immunohistochemistry. We divided the cases 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 = .012). Schlafen 11 expression correlated significantly with the expression of luminal subtype marker GATA3. Multivariate analyses identified SLFN11 expression as an independent prognostic predictor (odds ratio, 0.32; 95% confidence interval, 0.11-0.91; P = .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 = .034). In vitro analyses using multiple BC cell lines confirmed that SLFN11 KO rendered cells resistant to cisplatin. The epigenetic modifying drugs 5-azacytidine and entinostat restored SLFN11 expression and resensitized 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., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2022
- Full Text
- View/download PDF