An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma

• Type of Material: Article
• Authors: Chen-Lei Wen, Shanghai Jiao Tong University; Ke Huang, Fudan University; Lu-Lu Jiang, Fudan University; Xiong-Xiong Lu, Shanghai Jiao Tong University; Yu-Ting Dai, Ruijin Hospital; Min-Min Shi, Shanghai Jiao Tong University; Xiao-Mei Tang, Shanghai Jiao Tong University; Qing-Bing Wang, Ruijin Hospital; Xiao-Dan Zhang, Fudan University; Peng-Hui Wang, Fudan University; Hui-Ti Li, Fudan University; Xiao-Xue Ruan, Fudan University; Li-Wen Wang, Shanghai Jiao Tong University; Xin-Jing Wang, Shanghai Jiao Tong University; Qian Wang, Emory University; Wei Lu, Fudan University; Xiao-Qiang Xiang, Fudan University; Xun Sun, Fudan University; Yan-Hui Xu, Fudan University; Lu-Hau Lai, Peking University; Qian Zhan, Shanghai Jiao Tong University; Hong-Wei Li, Shanghai Jiao Tong University; Cheng-Hong Peng, Shanghai Jiao Tong University; Jing Chen, Emory University; Jin-Yan Huang, Ruijin Hospital; De-Yong Ye, Fudan University; Sai-Juan Chen, Ruijin Hospital; Zhu Chen, Ruijin Hospital; Min Li, University of Oklahoma; Yuan Fang, Shanghai Jiao Tong University; Bai-Yong Shen, Shanghai Jiao Tong University; Lu Zhou, Fudan University
• Language: English
• Date: 2019-11-12
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: © 2019 National Academy of Sciences. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1914557116
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 116
• Issue: 46
• Start Page: 23264
• End Page: 23273
• Grant/Funding Information: Work in the L.Z. laboratory is supported by the National Natural Science Foundation of China (No. 21472026, 21877014, 91853206). Work in the Y.F. and B.-Y.S. laboratories was supported by the Shanghai Municipal Committee of Science and Technology (grant#: 15JC1402800), the National Natural Science Foundation of China (No. 81502695, 81802358, 81871906, 81672325), the Shanghai Municipal Education Commission (grant#: 14ZZ103), and the Shanghai Eastern Youth Scholar Program (to Y.F.; grant#: DQ2015010).
• Keywords: ERLOTINIB; PDAC; TARGETING CANCER METABOLISM; glycolysis; PGAM1 inhibitor; CELL-MIGRATION; Science & Technology; GEMCITABINE; Science & Technology - Other Topics; TUMORS; cancer metabolism; SWITCH; Multidisciplinary Sciences
• Research Categories: Biology, Cell; Health Sciences, Oncology; Education, Technology

Abstract

Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/ stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided “proof of concept” for the potential application of metabolic treatment in clinical practice.