Dasatinib causes keratinocyte apoptosis via inhibiting high mobility group Box 1-mediated mitophagy

Dasatinib, a second-generation BCR-ABL inhibitor, is currently used as first-line treatment for patients with chronic myeloid leukemia. However, dasatinib treatment increases the risk of severe cutaneous toxicity, which limits its long-term safe use in clinic. The underlying mechanism for dasatinib-induced cutaneous toxicity has not been clarified. In this study, we tested the toxicity of dasatinib on human immortal keratinocyte line (HaCaT) and normal human epidermal keratinocytes (NHEK). We found that dasatinib directly caused cytotoxicity on kera-tinocytes, which could be the explanation of the clinical characteristic of pathology. Mechanistically, dasatinib impaired mitophagy by downregulating HMGB1 protein level in keratinocytes, which led to the accumulation of dysfunctional mitochondria. Mitochondria-derived ROS caused DNA damage and cell apoptosis. More impor-tantly, we confirmed that overexpression of HMGB1 could reverse dasatinib-induced keratinocyte apoptosis, and preliminarily explored the intervention effect of saikosaponin A, which could increase HMGB1 expression, on cutaneous toxicity caused by dasatinib. Collectively, our study revealed that dasatinib induced keratinocyte apoptosis via inhibiting HMGB1-mediated mitophagy and saikosaponin A could be a viable strategy for pre-vention of dasatinib-induced cutaneous toxicity.

Automated summary

Dasatinib, a first-line treatment for chronic myeloid leukemia, has the limitation of severe cutaneous toxicity. This study revealed that dasatinib directly induced cytotoxicity on keratinocytes by inhibiting HMGB1-mediated mitophagy, leading to keratinocyte apoptosis. Saikosaponin A could be a potential strategy for preventing dasatinib-induced cutaneous toxicity.