Affiliation:
1. Department of Surgery, School of Medicine Southeast University Nanjing China
2. Department of Hepato‐Pancreatico‐Biliary Surgery Zhongda Hospital Southeast University Nanjing China
Abstract
AbstractBackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options. The PI3K/AKT/mTOR pathway is commonly activated in PDAC and plays a critical role in its progression.Methods and ResultsIn this study, the effect of taselisib (a selective PI3K inhibitor) on PDAC cell proliferation was investigated, and a significant decrease in viability was observed with increasing concentrations of taselisib. Differential analysis on samples from the Genotype–Tissue Expression and The Cancer Genome Atlas databases revealed 24 dysregulated PI3K/AKT/mTOR pathway‐related genes (PRGs). Unsupervised clustering‐based analysis of transcriptome cohorts revealed two clusters with high consistency between RNA‐seq and microarray cohorts. Cluster B had higher enrichment of immune cells, particularly CD8+ T cells, and lower levels of immunosuppressive Treg cells. Moreover, we investigated the relationship between drug sensitivity and different clusters and found that cluster A had a better response to PI3K/AKT/mTOR pathway‐related inhibitors and chemotherapy. Finally, cluster A exhibited significant activation of PI3K/AKT/mTOR and related oncogenic pathways, contributing to poor prognosis. The study also developed a risk score based on the expression profiles of PRGs and machine learning, which showed a significant increase in overall survival time among patients in the low‐risk group. Importantly, the PI3K/AKT/mTOR pathway could be used to better predict individual risk scores, as evidenced by stratified survival analysis.ConclusionsThese findings suggest that targeting the PI3K/AKT/mTOR pathway may have therapeutic potential in PDAC, and distinct pathway states, immune modulation and tumor microenvironments have prognostic value.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Jiangsu Province
Subject
Genetics (clinical),Drug Discovery,Genetics,Molecular Biology,Molecular Medicine
Cited by
1 articles.
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