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
  • 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: [email protected].
  • 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: [email protected].
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).
Products