2. Academic Validation
  3. Pharmacogenomics-based subtype decoded implications for risk stratification and immunotherapy in pancreatic adenocarcinoma

Pharmacogenomics-based subtype decoded implications for risk stratification and immunotherapy in pancreatic adenocarcinoma

  • Mol Med. 2025 Feb 19;31(1):62. doi: 10.1186/s10020-024-01049-6.
Xing Zhou # 1 2,  Yuhao Ba # 1,  Nuo Xu # 3,  Hui Xu 1,  Yuyuan Zhang 1,  Long Liu 4,  Siyuan Weng 1,  Shutong Liu 5,  Zhe Xing 6,  Shuang Chen 3,  Peng Luo 7,  Libo Wang 8,  Xinwei Han 9 10 11
Affiliations

Affiliations

  • 1 Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 2 Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 3 Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 5 School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, China.
  • 6 Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 7 Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 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, China. 13273026498@163.com.
  • 9 Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. fcchanxw@zzu.edu.cn.
  • 10 Interventional Institute of Zhengzhou University, Zhengzhou, Henan, China. fcchanxw@zzu.edu.cn.
  • 11 Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan, China. fcchanxw@zzu.edu.cn.
  • # Contributed equally.
PMID: 39972282 DOI: 10.1186/s10020-024-01049-6
Abstract

Background: With fatal malignant peculiarities and poor survival rate, outcomes of pancreatic adenocarcinoma (PAAD) were frustrated by non-response and even resistance to therapy due to heterogeneity across clinical patients. Nevertheless, pharmacogenomics has been developed for individualized-treatment and still maintains obscure in PAAD.

Methods: A total of 964 samples from 10 independent multi-center cohorts were enrolled in our study. With drug response data from the profiling of relative inhibition simultaneously in mixtures (PRISM) and genomics of drug sensitivity in Cancer (GDSC) databases, we established and validated multidimensionally three pharmacogenomics-classified subtypes using non-negative matrix factorization (NMF) and nearest template prediction (NTP) algorithms, separately. The heterogenous biological characteristics and precision medicine strategies among subtypes were further investigated.

Results: Three pharmacogenomics-classified subtypes after stable and reproducible validation, distinguished in six aspects of prognosis, biological peculiarities, immune landscapes, genomic variations, immunotherapy and individualized management strategies. Subtype 2 was close to immunocompetent phenotype and projected to immunotherapy; Subtype 3 held most favorable outcomes and metabolic pathways distinctively, promising to be treated with first-line agents. Subtype 1 with worst prognosis, was anticipated to chromosome instability (CIN) phenotype and resistant to chemotherapeutic agents. In addition, ITGB6 contributed to subtype 1 resistance to 5-fluorouracil, and knockdown of ITGB6 enhanced sensitivity to 5-fluorouracil in in vitro experiments. Ultimately, appropriate clinical stratified treatments were assigned to corresponding subtypes according to pharmacogenomic transcripts. Some limitations were not taken into account, thus needs to be supported by more research.

Conclusion: A span-new molecular subtype exploited for PAAD uncovered an insight into precise medication on ground of pharmacogenomics, and highly refined multiple clinical management strategies for specific patients.

Keywords

Immunotherapy; Molecular subtype; Pancreatic adenocarcinoma; Pharmacogenomics; Precision medicine.

Figures
Products