A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS-mutant pancreatic cancer. (28th August 2017)

• Record Type: Journal Article
• Authors: Zhao, Xiao; Wang, Xiuchao; Fang, Lijun; Lan, Chungen; Zheng, Xiaowei; Wang, Yongwei; Zhang, Yinlong; Han, Xuexiang; Liu, Shaoli; Cheng, Keman; Zhao, Ying; Shi, Jian; Guo, Jiayi; Hao, Jihui; Ren, He; Nie, Guangjun
• Is Part Of: Cancer letters. Volume 402(2017)
• Page Start: 61
• Page End: 70
• Publication Date: 2017-08-28
• Subjects: Yes-associated protein (YAP) -- RAF inhibitor -- Pancreatic ductal adenocarcinoma (PDAC) -- Combinational therapy -- Verteporfin; PDAC Pancreatic ductal adenocarcinoma -- YAP Yes-associated protein -- MAP mitogen-activated protein -- IHC immunohistochemical -- DMEM dulbecco's modified eagle media -- FBS fetal bovine serum -- qRT-PCR quantitative reverse transcription polymerase chain reaction -- EdU 5-ethynyl-2′-deoxyuridine -- PBS phosphate buffered solution -- DMSO dimethyl sulfoxide -- OS overall survival -- RFS relapse free survival -- IC50 50% inhibition concentration -- PanIN pancreatic intraepithelial neoplasia -- EGFR epidermal growth factor receptor; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.05.015
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: KRAS mutation is the most common genetic event in pancreatic cancer. Whereas KRAS itself has proven difficult to inhibit, agents that target key downstream signals of KRAS, such as RAF, are possibly effective for pancreatic cancer treatment. Because selective BRAF inhibitors paradoxically induce downstream signaling activation, a pan-RAF inhibitor, LY3009120 is a better alternate for KRAS-mutant tumor treatment. Here we explored a new combinational strategy using a YAP inhibitor and LY3009120 in pancreatic cancer treatment. We found that reduced YAP expression closely correlates with longer relapse-free and overall survival of patients. Stable knockdown of YAP significantly inhibited pancreatic cancer cell proliferation and tumor growth. In addition, LY3009120 exhibited a dramatically enhanced antitumor effect in combination with YAP knockdown. YAP depletion blocks the activation of a parallel AKT signal pathway after LY3009120 treatment. Finally, combination with a YAP inhibitor, verteporfin, significantly enhanced the antitumor efficacy of LY3009120. Collectively, our results demonstrate that genetic or pharmacological inhibition of YAP can increase sensitivity to LY3009120 in pancreatic cancer through blocking compensatory activation of a parallel AKT signal pathway, thereby validating a combinatorial approach for treating KRAS-mutant pancreatic cancer. Highlights: YAP expression level is a prognostic indicator in PDAC patients. YAP inhibition lowers pancreatic cancer cell proliferation and tumor growth. LY3009120 exhibits an enhanced antitumor effect in combination with YAP knockdown. YAP depletion blocks the parallel AKT signal activation after LY3009120 treatment. Combination with verteporfin dramatically enhanced the antitumor effect of LY3009120.