2. Academic Validation
  3. Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis

Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis

  • Pharmacol Res. 2023 Oct 14:197:106955. doi: 10.1016/j.phrs.2023.106955.
Shuai Tang 1,  Yichen Duan 2,  Tao Yuan 3,  Yuting Hu 4,  Liang Yuan 5,  Ning Shen 5,  Yixian Fu 5,  Congying Pu 5,  Xiaomin Wang 5,  Jun Xu 5,  Xiaojing Lan 5,  Ying Zheng 5,  Yu Zhou 4,  Hong Zhu 3,  Jian Ding 6,  Meiyu Geng 7,  Min Huang 8
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China; Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
  • 7 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China. Electronic address: mygeng@simm.ac.cn.
  • 8 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China. Electronic address: mhuang@simm.ac.cn.
PMID: 37820855 DOI: 10.1016/j.phrs.2023.106955
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies lacking effective therapies. KRAS mutations that occur in over 90% of PDAC are major oncogenic drivers of PDAC. The MAPK signaling pathway plays a central role in KRAS-driven oncogenic signaling. However, pharmacological inhibitors of the MAPK pathway are poorly responded in KRAS-mutant PDAC, raising a compelling need to understand the mechanism behind and to seek new therapeutic solutions. Herein, we perform a screen utilizing a library composed of 800 naturally-derived bioactive compounds to identify Natural Products that are able to sensitize KRAS-mutant PDAC cells to the MAPK inhibition. We discover that tetrandrine, a natural bisbenzylisoquinoline alkaloid, shows a synergistic effect with MAPK inhibitors in PDAC cells and xenograft models. Mechanistically, pharmacological inhibition of the MAPK pathway exhibits a double-edged impact on the TRAIL-death receptor axis, transcriptionally upregulating TRAIL yet downregulating its agonistic receptors DR4 and DR5, which may explain the limited therapeutic outcomes of MAPK inhibitors in KRAS-mutant PDAC. Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing Apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.

Keywords

AZD6244 (PubChem CID: 10127622); BVD-523 (PubChem CID: 11719003); Cycloheximide (PubChem CID: 6197); Death receptors; GDC0994 (PubChem CID: 71727581); KRAS; MAPK pathway; MG132 (PubChem CID: 45103781); Pancreatic ductal adenocarcinoma; TRAIL; Tetrandrine; Tetrandrine (PubChem CID: 73078) and Hydroxychloroquine Sulfate (PubChem CID: 12947); Z-VAD-FMK (PubChem CID: 5497174).

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