Combination of Vismodegib and Paclitaxel Enhances Cytotoxicity via Bak-mediated Mitochondrial Damage in EGFR-Mutant...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Epidermal growth factor receptor (EGFR) mutations are present in half of non-small cell lung cancer (NSCLC) patients.
• EGFR-mutant NSCLC exhibits distinct therapeutic responses compared to EGFR-wild-type (EGFR-WT) NSCLC.
• Hedgehog inhibitor vismodegib (Vis) previously enhanced paclitaxel (PTX)-induced cytotoxicity in EGFR-WT NSCLC by promoting apoptosis.

Purpose of the Study:

• To investigate the anticancer activity of the Vis and PTX combination in EGFR-mutant NSCLC cells.
• To elucidate the underlying molecular mechanisms of this combination treatment in EGFR-mutant NSCLC.
• To assess the potential of Vis and PTX as a therapeutic strategy for EGFR-mutant NSCLC.

Main Methods:

• Cell viability assessed using MTS/PMS activity and trypan blue exclusion assays.
• Apoptosis monitored via chromosome condensation, annexin V staining, and PARP/caspase-3 cleavage.
• Western blotting, ROS level monitoring, and mitochondrial status analysis were performed.

Main Results:

• Paclitaxel (PTX) induced hedgehog signaling, rendering EGFR-mutant cells insensitive to PTX-induced apoptosis by suppressing Bak.
• Vismodegib (Vis) enhanced PTX-induced Bak activation in EGFR-mutant cells.
• The combination treatment led to increased mitochondrial damage, reactive oxygen species (ROS) accumulation, and subsequent apoptosis.

Conclusions:

• The combination of Vis and PTX effectively induces apoptosis in EGFR-mutant NSCLC cells.
• This combination overcomes PTX resistance by enhancing Bak activation and mitochondrial damage.
• Vis and PTX represent a potential therapeutic strategy to improve PTX sensitivity in EGFR-mutant NSCLC.