Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant

Background Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor, approved by the FDA for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the most frequently observed adverse event with tyrosine kinase inhibitor therapy. In this study, we developed a reproduci...

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Bibliographic Details
Published in:Breast cancer (Tokyo, Japan) Japan), 2021, Vol.28 (1), p.99-109
Main Authors: Secombe, Kate R., Ball, Imogen A., Shirren, Joseph, Wignall, Anthony D., Keefe, Dorothy M., Bowen, Joanne M.
Format: Article
Language:English
Subjects:
Adjuvant treatment
Cancer
Cancer Research
Comparative analysis
Complications and side effects
Diarrhea
Drug approval
Drug therapy
Medicine
Medicine & Public Health
Oncology
Original Article
Surgery
Surgical Oncology
Tyrosine
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Summary:Background Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor, approved by the FDA for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the most frequently observed adverse event with tyrosine kinase inhibitor therapy. In this study, we developed a reproducible model for neratinib-induced diarrhea in male and female rats. Methods At first, male rats were treated with neratinib at 15, 30 or 50 mg/kg or vehicle control via oral gavage for 28 days (total n  = 12). Secondly, we compared outcomes of male ( n  = 7) and female ( n  = 8) rats, treated with 50 mg/kg neratinib. Results Rats treated with a 50 mg/kg daily dose of neratinib had a reproducible and clinically relevant level of diarrhea and therefore was confirmed as an appropriate dose. Male rats treated with neratinib had significant changes to their gut microbiome. This included neratinib-induced increases in Ruminococcaceae ( P  = 0.0023) and Oscillospira ( P  = 0.026), and decreases in Blautia ( P  = 0.0002). On average, female rats experienced more significant neratinib-induced diarrhea (mean grade 1.526) compared with male rats (mean grade 1.182) ( P  
ISSN:1340-6868
1880-4233
DOI:10.1007/s12282-020-01133-9