School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia.
The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
Cancer Chemother Pharmacol. 2024 Oct;94(4):493-505. doi: 10.1007/s00280-024-04699-9. Epub 2024 Jul 13.
Neratinib, a small-molecule tyrosine kinase inhibitor (TKI) that irreversibly binds to human epidermal growth factor receptors 1, 2 and 4 (HER1/2/4), is an approved extended adjuvant therapy for patients with HER2-amplified or -overexpressed (HER2-positive) breast cancers. Patients receiving neratinib may experience mild-to-severe symptoms of gut toxicity including abdominal pain and diarrhoea. Despite being a highly prevalent complication in gut health, the biological processes underlying neratinib-induced gut injury, especially in the colon, remains unclear.
Real-time quantitative polymerase chain reaction (RT-qPCR) and histology were integrated to study the effect of, and type of cell death induced by neratinib on colonic tissues collected from female Albino Wistar rats dosed with neratinib (50 mg/kg) daily for 28 days. Additionally, previously published bulk RNA-sequencing and CRISPR-screening datasets on human glioblastoma SF268 cell line and glioblastoma T895 xenograft, and mouse TBCP1 breast cancer cell line were leveraged to elucidate potential mechanisms of neratinib-induced cell death.
The severity of colonic epithelial injury, especially degeneration of surface lining colonocytes and infiltration of immune cells, was more pronounced in the distal colon than the proximal colon. Sequencing showed that apoptotic gene signature was enriched in neratinib-treated SF268 cells while ferroptotic gene signature was enriched in neratinib-treated TBCP1 cells and T895 xenograft. However, we found that ferroptosis, but less likely apoptosis, was a potential histopathological feature underlying colonic injury in rats treated with neratinib.
Ferroptosis is a potential feature of neratinib-induced colonic injury and that targeting molecular machinery governing neratinib-induced ferroptosis may represent an attractive therapeutic approach to ameliorate symptoms of gut toxicity.
奈拉替尼是一种小分子酪氨酸激酶抑制剂（TKI），可不可逆地结合人表皮生长因子受体 1、2 和 4（HER1/2/4），已被批准用于治疗 HER2 扩增或过表达（HER2 阳性）乳腺癌患者的扩展辅助治疗。接受奈拉替尼治疗的患者可能会出现轻度至重度胃肠道毒性症状，包括腹痛和腹泻。尽管胃肠道毒性是一种高发并发症，但奈拉替尼诱导胃肠道损伤的生物学过程，尤其是在结肠中，仍不清楚。
实时定量聚合酶链反应（RT-qPCR）和组织学相结合，研究了奈拉替尼（50mg/kg）每日给药 28 天对雌性白化 Wistar 大鼠结肠组织的影响及诱导的细胞死亡类型。此外，还利用先前发表的关于人胶质母细胞瘤 SF268 细胞系和胶质母细胞瘤 T895 异种移植瘤以及小鼠 TBCP1 乳腺癌细胞系的批量 RNA 测序和 CRISPR 筛选数据集，阐明奈拉替尼诱导细胞死亡的潜在机制。
结肠上皮损伤的严重程度，尤其是表面衬里结肠细胞的退化和免疫细胞的浸润，在远端结肠比近端结肠更为明显。测序结果显示，凋亡基因特征在奈拉替尼处理的 SF268 细胞中富集，而铁死亡基因特征在奈拉替尼处理的 TBCP1 细胞和 T895 异种移植瘤中富集。然而，我们发现铁死亡，而不是凋亡，可能是奈拉替尼治疗大鼠结肠损伤的潜在组织病理学特征。
铁死亡是奈拉替尼诱导结肠损伤的潜在特征，靶向调控奈拉替尼诱导铁死亡的分子机制可能代表一种有吸引力的治疗方法，以改善胃肠道毒性症状。
