Background: Transitional cell carcinoma of the bladder (TCC) arises from the cells lining the bladder and accounts for 90% of bladder cancers. Current standard of care for muscle-invasive TCC is surgery with perioperative cisplatin-based chemotherapy regimens. Some tumors are quite sensitive to cisplatin but others either acquire resistance or are refractory. A reduced drug availability, an increased efficacy of the DNA damage repair machinery or defects in the apoptotic process are the main mechanisms involved in cisplatin resistance. The Hippo tumor suppressor pathway controls multiple cellular functions that are important for tumorigenesis and drug-resistance, including proliferation, apoptosis and oxidative stress regulation. Specifically, the overexpression of Yes-associated protein (YAP), one of the two repressed-targets of this pathway, prevents tumor necrosis factor-induced apoptosis in mouse liver and protects cancer cells from chemotherapy-induced apoptosis. Intriguingly, this transcriptional co-activator has been shown to be involved in bladder cancer progression and to be a biomarker for poor prognosis of patients with TCC. Furthermore, in ovarian cancer, YAP has been shown to confer resistance to cisplatin. Thus, we hypothesized that YAP may be involved in cisplatin resistance in bladder cancer and could predict drug response in TCC patients. Methods: Cisplatin activity and YAP protein expression and localization were analyzed in different in vitro and in vivo models of TCC: 1) Collection of bladder cancer cell lines, genetically manipulated by knocking-down or overexpressing YAP; 2) Cell line models of cisplatin resistance, obtained by long term continuous in vitro exposure to increasing drug concentrations; 3) Two TCC patient derived xenograft (PDX) models and derived primary cells (RP-B-01 and RP-B-02) with different intrinsic sensitivity to cisplatin. Furthermore, by continuous in vivo cisplatin treatment (2.5 to 5 mg/Kg, 1x/week, i.p.), we are currently establishing a cisplatin resistant RP-B-02 model. In vitro cisplatin effect was evaluated in apoptosis, proliferation and colony formation assays. Results: YAP expression and nuclear localization was inversely correlated with cisplatin sensitivity in TCC cell lines. Cisplatin-resistant TCC cell lines expressed higher YAP than parental counterparts. Cisplatin-induced apoptosis was significantly increased by YAP knockdown in T24 cell line. In vivo cisplatin treatment showed a greater anti-tumor effect in the low YAP-expressing RP-B-02 model as compared to the high YAP-expressing RP-B-01 tumors. Expression of YAP in human TCC specimens will be also presented. Summary: Overall, these data suggest that YAP has a role in bladder cancer response to cisplatin and highlights the potential therapeutic application of YAP as a biomarker of cisplatin sensitivity in TCC patients.
Citation Format: Eric Stefano Ciamporcero, He Shen, Sreenivasulu Chintala, Swathi Ramakrishnan, Sheng Yu Ku, Kiersten M. Miles, Stefania Pizzimenti, Candace Johnson, Jianmin Zhang, Giuseppina Barrera, Roberto Pili. Hippo pathway effector Yes-associated protein and cisplatin resistance in transitional cell carcinoma of the bladder. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3754. doi:10.1158/1538-7445.AM2014-3754