1. Academic Validation
  2. Sulindac (K-80003) with nab-paclitaxel and gemcitabine overcomes drug-resistant pancreatic cancer

Sulindac (K-80003) with nab-paclitaxel and gemcitabine overcomes drug-resistant pancreatic cancer

  • Mol Cancer. 2024 Sep 30;23(1):215. doi: 10.1186/s12943-024-02128-2.
Cheng-Ke Xie # 1 2 Cheng-Yu Liao # 1 2 3 Hong-Yi Lin # 1 2 Yong-Ding Wu # 1 2 Feng-Chun Lu 4 Xiao-Xiao Huang 1 2 3 Zu-Wei Wang 1 2 3 Ge Li 5 Cai-Feng Lin 1 2 3 Jian-Fei Hu 1 2 Yin-Hao Chen 1 2 Qiao-Wei Li 1 6 7 Li-Qun Chen 8 9 Hui-Xing Chen 10 11 Shi Chen 12 13 14 15 16
Affiliations

Affiliations

  • 1 Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China.
  • 2 Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China.
  • 3 Fuzhou University, Fuzhou, 350001, China.
  • 4 Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
  • 5 Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
  • 6 Fujian Provincial Center for Geriatrics, Fuzhou, 350001, China.
  • 7 Fujian Key Laboratory of Geriatrics, Fuzhou, 350001, China.
  • 8 College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108, China. lqchen@fzu.edu.cn.
  • 9 Institute of Applied Genomics, Fuzhou University, Fuzhou, 350108, China. lqchen@fzu.edu.cn.
  • 10 Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China. chenhuixing@163.com.
  • 11 Fujian Medical University Cancer Center, Fuzhou, 350001, China. chenhuixing@163.com.
  • 12 Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China. wawljwalj@163.com.
  • 13 Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China. wawljwalj@163.com.
  • 14 Fuzhou University, Fuzhou, 350001, China. wawljwalj@163.com.
  • 15 Fujian Provincial Center for Geriatrics, Fuzhou, 350001, China. wawljwalj@163.com.
  • 16 Fujian Key Laboratory of Geriatrics, Fuzhou, 350001, China. wawljwalj@163.com.
  • # Contributed equally.
Abstract

The Nab-paclitaxel combined with gemcitabine (AG) regimen is the main chemotherapy regimen for pancreatic Cancer, but drug resistance often occurs. Currently, the ability to promote sensitization in drug-resistant cases is an important clinical issue, and the strategy of repurposing conventional drugs is a promising strategy. This study aimed to identify a classic drug that targets chemotherapy resistance's core signaling pathways and combine it with the AG regimen to enhance chemosensitivity. We also aimed to find reliable predictive biomarkers of drug combination sensitivity. Using RNA Sequencing, we found that abnormal PI3K/Akt pathway activation plays a central role in mediating resistance to the AG regimen. Subsequently, through internal and external verification of randomly selected AG-resistant patient-derived Organoid (PDO) and PDO xenograft models, we discovered for the first time that the classic anti-inflammatory drug sulindac K-80003, an inhibitor of the PI3K/Akt pathway that we focused on, promoted sensitization in half (14/28) of AG-resistant pancreatic ductal adenocarcinoma cases. Through RNA-sequencing, multiplex immunofluorescent staining, and immunohistochemistry experiments, we identified cFAM124A as a novel biomarker through which sulindac K-80003 promotes AG sensitization. Its role as a sensitization marker is explained via the following mechanism: cFAM124A enhances both the mRNA expression of Cathepsin L and the activity of the Cathepsin L enzyme. This dual effect stimulates the cleavage of RXRα, leading to large amounts of truncated RXRα, which serves as a direct target of K-80003. Consequently, this process results in the pathological activation of the PI3K/Akt pathway. In summary, our study provides a new treatment strategy and novel biological target for patients with drug-resistant pancreatic Cancer.

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