Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E-Dependent Pyroptosis in Pancreatic...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Mitogen-activated protein kinase kinase (MEK) mutations are common in pancreatic ductal adenocarcinoma (PDAC).
• MEK inhibitors can paradoxically activate protein kinase B (AKT), limiting their efficacy.
• Gasdermin E (GSDME) is overexpressed in PDAC and linked to cell death pathways.

Purpose of the Study:

• To investigate the efficacy of combining trametinib with neobractatin (NBT) for PDAC treatment.
• To elucidate the underlying molecular mechanisms of the combination therapy.
• To evaluate the therapeutic potential of this combination in preclinical models.

Main Methods:

• Cell viability assays and induction of pyroptosis and apoptosis.
• RNA sequencing (RNA-seq) to identify targeted pathways.
• Western blotting to analyze protein expression and signaling pathways.
• MicroRNA sequencing and reactive oxygen species (ROS) assays.
• In vivo tumor xenograft studies comparing combination therapy with gemcitabine.

Main Results:

• The combination of trametinib and NBT significantly inhibited PDAC cell growth and tumor progression.
• The treatment induced GSDME-mediated pyroptosis and apoptosis.
• The combination suppressed the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway by reducing AKT phosphorylation and disrupting mTORC2 signaling.
• Upregulation of miR-149-5p and increased intracellular ROS were observed, with ROS mediating the anti-cancer effects.
• Combination therapy demonstrated superior efficacy compared to gemcitabine in vivo.

Conclusions:

• Combining NBT with trametinib offers a novel therapeutic strategy for PDAC by inducing pyroptosis and apoptosis.
• The mechanism involves ROS generation, AKT pathway inhibition, and GSDME activation.
• This combination presents a promising preclinical basis for developing new PDAC treatments.