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

Shuai Tang; Yichen Duan; Tao Yuan; Yuting Hu; Liang Yuan; Ning Shen; Yixian Fu; Congying Pu; Xiaomin Wang; Jun Xu; Xiaojing Lan; Ying Zheng; Yu Zhou; Hong Zhu; Jian Ding; Meiyu Geng; Min Huang

doi:10.1016/j.phrs.2023.106955

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

Pharmacol Res. 2023 Nov:197:106955. doi: 10.1016/j.phrs.2023.106955. Epub 2023 Oct 14.

Authors

Shuai Tang¹, Yichen Duan², Tao Yuan³, Yuting Hu⁴, Liang Yuan⁵, Ning Shen⁵, Yixian Fu⁵, Congying Pu⁵, Xiaomin Wang⁵, Jun Xu⁵, Xiaojing Lan⁵, Ying Zheng⁵, Yu Zhou⁴, Hong Zhu³, Jian Ding⁶, Meiyu Geng⁷, Min Huang⁸

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).

MeSH terms

Benzylisoquinolines* / pharmacology
Benzylisoquinolines* / therapeutic use
Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Humans
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins p21(ras) / genetics
Receptors, Death Domain

Substances

tetrandrine
Proto-Oncogene Proteins p21(ras)
Benzylisoquinolines
Protein Kinase Inhibitors
Receptors, Death Domain
KRAS protein, human