Prognostic impact of Schlafen 11 in bladder cancer patients treated with platinum‐based chemotherapy

• Published in: Cancer science 2022-02, Vol.113 (2), p.784-795
• Main Authors: Taniyama, Daiki, Sakamoto, Naoya, Takashima, Tsuyoshi, Takeda, Masahiko, Pham, Quoc Thang, Ukai, Shoichi, Maruyama, Ryota, Harada, Kenji, Babasaki, Takashi, Sekino, Yohei, Hayashi, Tetsutaro, Sentani, Kazuhiro, Pommier, Yves, Murai, Junko, Yasui, Wataru
• Format: Article
• Language: English
• Subjects: Aged; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Azacitidine - pharmacology; Azacytidine; Benzamides - pharmacology; biomarker; Biomarkers; Biomarkers, Tumor - metabolism; Bladder cancer; Cancer therapies; Carboplatin; Cell Line, Tumor; Chemotherapy; Chemotherapy, Adjuvant; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; CRISPR; Cytokeratin; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug Synergism; Drugs; Epigenetics; Female; GATA-3 protein; GATA3 Transcription Factor - metabolism; Humans; Immunohistochemistry; Male; Medical prognosis; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original; Patients; Platinum; Platinum - pharmacology; Platinum - therapeutic use; Prognosis; Prostate; Pyridines - pharmacology; SLFN11; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - mortality; Urinary Bladder Neoplasms - surgery
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15207

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. Schlafen 11 (SLFN11) is a predictive biomarker for bladder cancer patients who undergo platinum‐based chemotherapy. A combination of epigenetic modifiers could rescue bladder cancer patients who are refractory to platinum derivatives, by reactivating SLFN11 expression.