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

Autor: Nguyen TPM; School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia. phuminhtrietthomas.nguyen@unimelb.edu.au.; The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia. phuminhtrietthomas.nguyen@unimelb.edu.au.; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia. phuminhtrietthomas.nguyen@unimelb.edu.au., Woods SL; Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.; Precision Cancer Medicine, South Australian Health and Medical Research Institute, Adelaide, SA, Australia., Secombe KR; School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia., Tang S; School of Life and Environmental Sciences, The University of Sydney, Sydney, Australia., Elz AS; School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia.; Clinical and Health Sciences, University of South Australia, Adelaide, Australia., Ayton S; The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia., Finnie J; Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia., Nagpal A; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, 3000, Australia., Pouliot N; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia.; Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia., Bowen JM; School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia. joanne.bowen@adelaide.edu.au.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, 3000, Australia. joanne.bowen@adelaide.edu.au.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2024 Oct; Vol. 94 (4), pp. 493-505. Date of Electronic Publication: 2024 Jul 13.
DOI: 10.1007/s00280-024-04699-9
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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