2. Academic Validation
  3. Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis

Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis

  • J Exp Clin Cancer Res. 2023 May 4;42(1):111. doi: 10.1186/s13046-023-02671-8.
Tianxing Zhou # 1,  Yongjie Xie # 1,  Xupeng Hou # 1 2,  Weiwei Bai 1,  Xueyang Li 1 2,  Ziyun Liu 1 2,  Quan Man 1 3,  Jingyan Sun 2,  Danqi Fu 1,  Jingrui Yan 1,  Zhaoyu Zhang 1,  Yifei Wang 1,  Hongwei Wang 1,  Wenna Jiang 4,  Song Gao 1,  Tiansuo Zhao 1,  Antao Chang 1,  Xiuchao Wang 1,  Hongxia Sun 5,  Xiufeng Zhang 6,  Shengyu Yang 7,  Chongbiao Huang 8 9,  Jihui Hao 10,  Jing Liu 11 12
Affiliations

Affiliations

  • 1 Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China.
  • 2 Department of Breast Oncoplastic Surgery and Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, PR China.
  • 3 Department of Hepatopancreatobiliary Surgery, Tongliao City Hospital, Tongliao, 028000, Inner Mongolia, China.
  • 4 Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
  • 5 Beijing National Laboratory for Molecular Sciences (BNLMS), State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, P. R. China.
  • 6 College of Chemical Engineering, North China University of Science and Technology, Tangshan, 063210, China.
  • 7 Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA.
  • 8 Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China. chhuang@tmu.edu.cn.
  • 9 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China. chhuang@tmu.edu.cn.
  • 10 Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China. haojihui@tjmuch.com.
  • 11 Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China. piano_solo@163.com.
  • 12 Department of Breast Oncoplastic Surgery and Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, PR China. piano_solo@163.com.
  • # Contributed equally.
PMID: 37143164 DOI: 10.1186/s13046-023-02671-8
Abstract

Background: Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance.

Methods: We established a bio-bank of human PDAC Organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid Apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived Organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism.

Results: High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy.

Conclusions: Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.

Keywords

High-throughput drug screening; Irbesartan; Organoids; Pancreatic cancer; c-Jun.

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