Int J Med Sci 2022; 19(2):286-298. doi:10.7150/ijms.68404 This issue

Research Paper

Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer

Shi-lei Liu*,1,2, Hai-bin Liang*,1,2, Zi-yi Yang*,1,2, Chen Cai1,2, Zi-you Wu1,2, Xiang-song Wu1,2, Ping Dong1,2, Mao-lan Li1✉, Lei Zheng3✉, Wei Gong1✉

1. Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
2. Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai 200092, China
3. The Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
*These authors contributed equally to this work.

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Citation:
Liu Sl, Liang Hb, Yang Zy, Cai C, Wu Zy, Wu Xs, Dong P, Li Ml, Zheng L, Gong W. Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer. Int J Med Sci 2022; 19(2):286-298. doi:10.7150/ijms.68404. Available from https://www.medsci.org/v19p0286.htm

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Abstract

Graphic abstract

Pancreatic cancer (PC) is one of the most fatal and chemoresistant malignancies with a poor prognosis. The current therapeutic options for PC have not achieved satisfactory results due to drug resistance. Therefore, it is urgent to develop novel treatment strategies with enhanced efficacy. This study sought to investigate the anticancer effect of gemcitabine and XCT790, an estrogen-related receptor alpha (ERRα) inverse agonist, as monotherapies or in combination for the treatment of PC. Here we demonstrated that the drug combination synergistically suppressed PC cell viability, its proliferative, migratory, invasive, apoptotic activities, and epithelial-to-mesenchymal transition (EMT), and it triggered G0/G1 cell cycle arrest and programmed cell death in vitro. In addition, in vivo assays using xenograft and mini-PDX (patient-derived xenograft) models further confirmed the synergistic antitumor effect between gemcitabine and XCT790 on PC. Mechanistically, gemcitabine and XCT790 suppressed PC by inhibiting ERRα and MEK/ERK signaling pathway. In conclusion, our current study demonstrated for the first time that gemcitabine combined with XCT790 displayed synergistic anticancer activities against PC, suggesting that their combination might be a promising treatment strategy for the therapy of PC.

Keywords: Gemcitabine, XCT790, Combination therapy, Pancreatic cancer, Mini-PDX