酪氨酸激酶抑制剂（TKIs）常被用于抗癌治疗，通常为长期应用。其中许多治疗方案会引起心脏毒性反应，治愈难度较大。我们的目标是澄清TKI诱导心脏毒性的分子机制，从而为治疗不良的心脏并发症寻找潜在的靶点。我们选择了具有不同心脏毒性水平的八种TKIs，并对人类心肌细胞对不同剂量和时间的TKIs的表型和转录组反应进行了分析和描述。我们在心肌细胞和大鼠心脏中验证了调节三种TKIs诱导的心脏毒性的压力反应和信号通路。通过对细胞存活率、收缩性和呼吸功能的影响进行测量，确定了八种TKIs的毒性等级，这与数据库或文献得出的结果大致一致，表明人类心肌细胞是研究心脏毒性的良好细胞模型。使用不同毒性级别的选定TKI治疗人类心肌细胞时，数据可以分为7个簇，主要是单药簇，药物特异性对转录组的影响优于剂量、时间或毒性依赖性的影响。其中三种TKIs（阿法替尼、泊沙尼布和索拉非尼）的两个簇具有最丰富的内质网应激（ERS）通路。所有三种TKIs都在大鼠初级心肌细胞中诱导了ERS，泊沙尼布在7天的药物治疗后激活了ERS下游的IRE1α-XBP1s轴。为寻找ERS的潜在触发因素，我们发现这三种TKIs会产生短暂的反应性氧物种，随后出现脂质过氧化。抑制ERS下游的PERK或IRE1α可以阻止TKI诱导的心脏损伤，包括诱导心脏胎儿和促炎性基因，而不会导致更多的细胞死亡。我们的数据包含了人类心肌细胞对八种TKIs的表型和转录反应的丰富信息，并揭示了在调节心脏毒性方面的潜在分子机制。多种TKIs激活ERS并通过促进炎症因子和心脏胎儿基因的表达来导致心脏毒性。ERS诱导的炎症是缓解泊沙尼布和索拉非尼诱导的心脏毒性的有前途的治疗靶点。©2023年作者。

Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics often prescribed for long-term treatment. Many of these treatments cause cardiotoxicity with limited cure. We aim to clarify molecular mechanisms of TKI-induced cardiotoxicity so as to find potential targets for treating the adverse cardiac complications.Eight TKIs with different levels of cardiotoxicity reported are selected. Phenotypic and transcriptomic responses of human cardiomyocytes to TKIs at varying doses and times are profiled and analyzed. Stress responses and signaling pathways that modulate cardiotoxicity induced by three TKIs are validated in cardiomyocytes and rat hearts.Toxicity rank of the eight TKIs determined by measuring their effects on cell viability, contractility, and respiration is largely consistent with that derived from database or literature, indicating that human cardiomyocytes are a good cellular model for studying cardiotoxicity. When transcriptomes are measured for selected TKI treatments with different levels of toxicity in human cardiomyocytes, the data are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib, and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress (ERS). All three TKIs induce ERS in rat primary cardiomyocytes and ponatinib activates the IRE1α-XBP1s axis downstream of ERS in the hearts of rats underwent a 7-day course of drug treatment. To look for potential triggers of ERS, we find that the three TKIs induce transient reactive oxygen species followed by lipid peroxidation. Inhibiting either PERK or IRE1α downstream of ERS blocks TKI-induced cardiac damages, represented by the induction of cardiac fetal and pro-inflammatory genes without causing more cell death.Our data contain rich information about phenotypic and transcriptional responses of human cardiomyocytes to eight TKIs, uncovering potential molecular mechanisms in modulating cardiotoxicity. ER stress is activated by multiple TKIs and leads to cardiotoxicity through promoting expression of pro-inflammatory factors and cardiac fetal genes. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity.© 2023. The Author(s).