Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Abstract

Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy.Experimental Design: Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity.Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel.Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201.

STAT3 activation confers trastuzumab‐emtansine (T‐DM1) resistance in HER2‐positive breast cancer

“…Aberrant STAT3 activation has been implicated in trastuzumab resistance in HER2‐positive breast and gastric cancers . Moreover, STAT3 is involved in resistance to antimicrotubule agents, and the combination of taxane and a STAT3 inhibitor was showed to exert enhanced cytotoxicity towards STAT3‐dependent cell lines . The present study first showed that STAT3 is aberrantly activated in cells exposed to long‐term treatment with T‐DM1 and confers cells resistance.…”

“…36 Moreover, STAT3 is involved in resistance to antimicrotubule agents, and the combination of taxane and a STAT3 inhibitor was showed to exert enhanced cytotoxicity towards STAT3-dependent cell lines. 37,38 The present study first showed that STAT3 is aberrantly activated in cells exposed to long- Signal transducer and activator of transcription 3 (STAT3) activation was measured on western blotting. D, BT-474 and BT-474/KR cells were cultured separately, and lysates were mixed at a 1:1 ratio, or BT-474 and BT-474/KR cells were co-cultured at a 1:1 ratio.…”

Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we?

“…In urothelial carcinoma and bladder carcinoma, S3I-201 overcame resistance to paclitaxel and cisplatin (W. J. Wang, et al, 2016). Additionally, S3I-201 sensitized esophageal squamous cell carcinoma to radiation (C. Zhang, et al, 2014).…”

Inhibition of REDD1 Sensitizes Bladder Urothelial Carcinoma to Paclitaxel by Inhibiting Autophagy

“…Recent phase III clinical trials have found that a PCG (paclitaxel plus cisplatin plus gemcitabine) regimen, consisting of the addition of paclitaxel to a standard chemotherapy regimen of cisplatin plus gemcitabine (GC), can improve the overall response rate and overall survival rate of patients with BUC (7). However, acquired or de novo resistance to paclitaxel limits its clinical application in the treatment of BUC, and the identification of approaches to sensitize BUC to paclitaxel remains a significant clinical challenge (8,9).…”