Decreased HMGB1 expression contributed to cutaneous toxicity caused by lapatinib

Area of Science:

• Oncology
• Dermatology
• Molecular Biology

Background:

• Lapatinib, an EGFR/HER2 inhibitor, causes significant cutaneous toxicity, limiting its clinical use.
• The precise mechanisms underlying lapatinib-induced skin toxicity remain unclear, hindering effective management strategies.

Purpose of the Study:

• To elucidate the molecular mechanisms of lapatinib-induced cutaneous toxicity.
• To identify potential therapeutic targets for mitigating lapatinib's adverse skin reactions.

Main Methods:

• Investigated lapatinib's effects on keratinocyte apoptosis, DNA damage, and inflammatory responses in vitro and in vivo.
• Assessed the role of High Mobility Group Box 1 (HMGB1) in lapatinib toxicity.
• Evaluated the therapeutic potential of saikosaponin A in preventing lapatinib-induced skin toxicity.

Main Results:

• Lapatinib induces keratinocyte apoptosis via mitochondrial dysfunction and DNA damage.
• Lapatinib triggers aberrant immune responses and inflammatory factor release.
• Downregulation of HMGB1 is critical for lapatinib-induced toxicity; HMGB1 overexpression confers protection.
• Saikosaponin A restores HMGB1 expression, alleviating lapatinib-induced DNA damage and keratinocyte apoptosis, and preventing toxicity in mice.

Conclusions:

• Lapatinib-induced cutaneous toxicity involves mitochondrial dysfunction, DNA damage, keratinocyte apoptosis, and inflammation, mediated by HMGB1 downregulation.
• Restoring HMGB1 expression or utilizing saikosaponin A represents a promising strategy for preventing lapatinib-related skin adverse drug reactions.