Ferroptosis - a potential feature underlying neratinib-induced colonic epithelial injury

Nguyen, TPM; Woods, SL; Secombe, KR; Tang, S; Elz, AS; Ayton, S; Finnie, J; Nagpal, A; Pouliot, N; Bowen, JM

Author(s): Nguyen, TPM; Woods, SL; Secombe, KR; Tang, S; Elz, AS; Ayton, S; Finnie, J; Nagpal, A; Pouliot, N; Bowen, JM;
Details: Publication Year 2024-10,Volume 94,Issue #4,Page 493-505
Journal Title: Cancer Chemotherapy and Pharmacology
Publication Type: Research article
Abstract: PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Publisher: Springer Nature
Keywords: Animals; *Ferroptosis/drug effects; Rats; Female; Humans; *Quinolines/pharmacology; *Rats, Wistar; *Colon/pathology/drug effects/metabolism; Cell Line, Tumor; Mice; Protein Kinase Inhibitors/pharmacology; Colonic injury; Ferroptosis; Gut toxicity; Neratinib
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1007/s00280-024-04699-9
Open Access at Publisher's Site: https://doi.org/10.1007/s00280-024-04699-9
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-03 03:37:17

Last Modified: 2024-10-03 03:37:33