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. Overall design: 3 Control Samples and 3 Lapatinib-treated Samples

拉帕替尼（Lapatinib）是一款广泛应用的双重表皮生长因子受体（Epidermal Growth Factor Receptor, EGFR）与ERBB2抑制剂，但其临床应用因皮疹这一EGFR抑制剂最常见的不良反应之一而受到严重限制。本研究基于RNA测序（RNA-sequencing）线索，发现拉帕替尼可诱导线粒体功能障碍，进而引发DNA损伤，最终导致角质形成细胞凋亡。机制层面，DNA修复蛋白高迁移率族蛋白B1（High Mobility Group Box 1, HMGB1）的表达下调在上述毒性反应进程中发挥了关键作用。研究发现，柴胡皂苷A可显著恢复HMGB1的转录水平，从而缓解拉帕替尼诱导的DNA损伤、抑制角质形成细胞凋亡，并进一步预防拉帕替尼所致小鼠皮肤毒性。总体实验设计：3份对照样本与3份拉帕替尼处理样本