RNA-seq analysis revealed that lapatinib-induced keratinocyte apoptosis is related to mitochondrial dysfunction and DNA damage

Lapatinib, a widely used dual EGFR and ERBB2 inhibitor, have been seriously limited due to skin rash, one of its most common adverse effects caused by EGFR inhibitors in clinical. Here, we found that lapatinib could induce mitochondrial dysfunction, lead to DNA damage and finally cause apoptosis of keratinocytes according to the RNA-sequencing clues. Mechanistically, downregulated expression of DNA repair protein HMGB1 played a critical role in these toxic reaction processes. We found that saikosaponin A could significantly rescue the reduced HMGB1 transcription, which could alleviate lapatinib-induced DNA damage, inhibit keratinocyte apoptosis and further prevent the cutaneous toxicity in mice caused by lapatinib. 3 Control Samples and 3 Lapatinib-treated Samples