Afatinib induces pro-survival autophagy and increases sensitivity to apoptosis in stem-like HNSCC cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Afatinib is a tyrosine kinase inhibitor (TKI) used for head and neck squamous cell carcinoma (HNSCC).
• Afatinib's antitumor effects involve apoptosis induction via mTORC1 suppression.
• The role of autophagy in afatinib's mechanism in HNSCC is not fully understood.

Purpose of the Study:

• To elucidate the mechanism and significance of afatinib-induced autophagy in HNSCC.
• To investigate the relationship between reactive oxygen species (ROS), REDD1-TSC1-mTORC1 signaling, and autophagy.
• To evaluate the therapeutic potential of combining afatinib with autophagy inhibitors, particularly against HNSCC stem cells.

Main Methods:

• Investigated afatinib's effects on autophagy in HNSCC cell lines.
• Utilized pharmacological and genetic inhibition of autophagy.
• Assessed apoptosis and autophagy levels in vitro and in vivo, including in stem-like HNSCC cells (CDH1 knockdown).
• Analyzed the REDD1-TSC1-mTORC1 signaling pathway and ROS generation.

Main Results:

• Afatinib induces autophagy in HNSCC cells by suppressing mTORC1 through the ROS-REDD1-TSC1 axis.
• Inhibition of autophagy sensitizes HNSCC cells to afatinib-induced apoptosis, indicating pro-survival autophagy.
• Afatinib induced greater apoptosis and less autophagy in stem-like HNSCC cells.
• Blocking autophagy enhances afatinib's efficacy against HNSCC stem cells.

Conclusions:

• Afatinib activates pro-survival autophagy in HNSCC via the ROS-REDD1-TSC1-mTORC1 pathway.
• Combining afatinib with autophagy inhibitors is a potential strategy to eradicate HNSCC, including cancer stem cells.
• Targeting autophagy may overcome resistance and improve clinical outcomes in HNSCC treatment.