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

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dc.contributor.authorSecombe, K.R.
dc.contributor.authorBall, I.A.
dc.contributor.authorShirren, J.
dc.contributor.authorWignall, A.D.
dc.contributor.authorKeefe, D.M.
dc.contributor.authorBowen, J.M.
dc.date.issued2021
dc.description.abstractBackground: 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 < 0.0001). Neratinib caused a reduction in percentage weight gain after 28 days of treatment in females (P = 0.0018) compared with vehicle controls. Females and males both showed instances of villus atrophy and fusion, most severely in the distal ileum. Serum neratinib concentration was higher in female rats compared to male rats (P = 0.043). Conclusions: A reproducible diarrhea model was developed in both female and male rats, which indicated that diarrhea pathogenesis is multifactorial, including anatomical disruption particularly evident in the distal ileum, and alterations in microbial composition.
dc.description.statementofresponsibilityKate R. Secombe, Imogen A. Ball, Joseph Shirren, Anthony D. Wignall, Dorothy M. Keefe, Joanne M. Bowen
dc.identifier.citationBreast Cancer, 2021; 28(1):99-109
dc.identifier.doi10.1007/s12282-020-01133-9
dc.identifier.issn1880-4233
dc.identifier.issn1880-4233
dc.identifier.orcidSecombe, K.R. [0000-0003-0716-238X]
dc.identifier.orcidBall, I.A. [0000-0002-9629-9064]
dc.identifier.orcidKeefe, D.M. [0000-0001-9377-431X]
dc.identifier.orcidBowen, J.M. [0000-0003-0876-0031]
dc.identifier.urihttps://hdl.handle.net/2440/145776
dc.language.isoen
dc.publisherSpringer
dc.rights© The Japanese Breast Cancer Society 2020
dc.source.urihttps://doi.org/10.1007/s12282-020-01133-9
dc.subjectTyrosine kinase inhibitors; Diarrhea; Breast cancer; Rat model; Neratinib
dc.subject.meshIntestinal Mucosa
dc.subject.meshIleum
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshRats
dc.subject.meshBreast Neoplasms
dc.subject.meshDisease Models, Animal
dc.subject.meshDiarrhea
dc.subject.meshQuinolines
dc.subject.meshReceptor, erbB-2
dc.subject.meshProtein Kinase Inhibitors
dc.subject.meshSex Factors
dc.subject.meshFemale
dc.subject.meshMale
dc.subject.meshGastrointestinal Microbiome
dc.titlePathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant.
dc.typeJournal article
pubs.publication-statusPublished

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