Decreased HMGB1 expression contributed to cutaneous toxicity caused by lapatinib
Decreased HMGB1 expression contributed to cutaneous toxicity caused by lapatinib
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HMGB1 表达减少导致拉帕替尼引起的皮肤毒性
DOI：
10.1016/j.bcp.2022.115105
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发表时间：
2022-05-26
影响因子：
5.8
通讯作者：
He，Qiaojun
中科院分区：
文献类型：
--
作者：
Jiang，Liyu;Zeng，Yan;He，Qiaojun
拉帕替尼是一种广泛使用的人表皮生长因子受体1(EGFR/ErbB1)和人表皮生长因子受体2(HER2/ERBB2)的双重抑制剂，由于皮肤毒性，其应用受到严重限制。然而，拉帕替尼引起皮肤毒性的具体机制尚不清楚，导致缺乏有效的策略来提高临床安全性。在这里，我们发现拉帕替尼可以导致线粒体功能障碍，导致DNA损伤，最终导致角质形成细胞凋亡。此外，我们还发现，拉帕替尼在体内外均能诱导异常免疫反应，促进炎症因子的释放。从机制上讲，DNA修复蛋白HMGB1的表达下调在这些毒性反应过程中发挥了关键作用。HMGB1过表达抑制角质形成细胞的凋亡和炎症反应。因此，恢复HMGB1的表达可能是对抗拉帕替尼皮肤毒性的有效药物。最后，我们发现柴胡皂苷A可以显著修复HMGB1转录的下调，从而减轻拉帕替尼诱导的DNA损伤，抑制角质形成细胞的凋亡，从而进一步预防拉帕替尼的毒性。总之，我们的研究可能会给临床医生和肿瘤患者带来新的希望，并为预防EGFR抑制剂引起的皮肤不良反应提供新的曙光。
The application of lapatinib, a widely used dual inhibitor of human epidermal growth factor receptor 1 (EGFR/ERBB1) and 2 (HER2/ERBB2), has been seriously limited due to cutaneous toxicity. However, the specific mechanism of lapatinib-induced cutaneous toxicity has not been clarified, leading to the lack of an effective strategy to improve clinical safety. Here, we found that lapatinib could induce mitochondrial dysfunction, lead to DNA damage and ultimately cause apoptosis of keratinocytes. In addition, we found that lapatinib could induce an aberrant immune response and promote the release of inflammatory factorsin vitroandin vivo. Mechanistically, downregulated expression of the DNA repair protein HMGB1 played a critical role in these toxic reaction processes. Overexpression of HMGB1 inhibited keratinocyte apoptosis and inflammatory reactions. Therefore, restoring HMGB1 expression might be an effective remedy against lapatinib-induced cutaneous toxicity. Finally, 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 toxicity of lapatinib in mice. Collectively, our study might bring new hope to clinicians and tumor patients and shed new light on the prevention of cutaneous adverse drug reactions induced by EGFR inhibitors.