Simultaneous targeting PI3K and PERK pathways promotes cell death and improves the clinical prognosis in esophageal...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• The phosphoinositide 3-kinase (PI3K) pathway is a critical target in cancer therapy, but its specific role and mechanisms in esophageal squamous cell carcinoma (ESCC) remain incompletely understood.
• Analysis of The Cancer Genome Atlas (TCGA) datasets reveals significant upregulation of PI3Ks in human ESCC tissues compared to non-cancerous tissues.
• Alterations in the PI3K pathway demonstrably impact overall patient survival in ESCC, but not in esophageal adenocarcinoma (EAC).

Purpose of the Study:

• To investigate the therapeutic potential of targeting the PI3K pathway and its interplay with the PKR-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α)/activating transcription factor 4 (ATF4) pathway in ESCC.
• To evaluate the efficacy of dual targeting of PI3K and PERK pathways as a novel therapeutic strategy for ESCC.

Main Methods:

• Utilized TCGA datasets for analyzing PI3K expression levels and their correlation with patient survival in ESCC and EAC.
• Employed the PI3K inhibitor LY294002 to assess its effects on the canonical mammalian target of rapamycin (mTOR) and noncanonical PERK/eIF2α/ATF4 pathways in ESCC.
• Investigated the impact of PERK inhibition using siRNA and the small molecule inhibitor GSK2656157 on ESCC cell growth, colony formation, and apoptosis.
• Assessed the synergistic effects of combined PI3K and PERK pathway inhibition on ESCC progression.

Main Results:

• The PI3K inhibitor LY294002 effectively inhibited the mTOR pathway and suppressed ESCC growth with minimal toxicity to normal cells.
• LY294002 also demonstrated inhibitory effects on the noncanonical PERK/eIF2α/ATF4 pathway in ESCC.
• Both siRNA-mediated PERK knockdown and the PERK inhibitor GSK2656157 significantly inhibited ESCC growth.
• GSK2656157 potentiated the inhibitory effects of LY294002 on ESCC cell growth, colony formation, and apoptosis induction.
• Dual high expression of PI3K and PERK pathways in ESCC patients correlated with a more significant difference in overall survival (OS) compared to PI3K pathway expression alone.

Conclusions:

• The PI3K pathway is significantly upregulated in ESCC and plays a crucial role in patient survival.
• Dual targeting of the PI3K and PERK pathways presents a promising therapeutic strategy for improving clinical prognosis and treatment outcomes in ESCC patients.
• Combined inhibition of PI3K and PERK pathways offers a potential avenue for enhanced anti-tumor efficacy in ESCC.