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Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model

Abstract

Purpose

Neratinib is an irreversible pan-ErbB tyrosine kinase inhibitor used for the extended adjuvant treatment of early-stage HER2-positive breast cancer. Its use is associated with the development of severe diarrhea in up to 40% of patients in the absence of proactive management. We previously developed a rat model of neratinib-induced diarrhea and found inflammation and anatomical disruption in the ileum and colon. Here we tested whether anti-diarrheal interventions, budesonide and colesevelam, can reduce neratinib-induced diarrhea and intestinal pathology.

Methods

Rats were treated with 50 mg/kg neratinib via oral gavage for 14 or 28 days (total n = 64). Body weight and diarrhea severity were recorded daily. Apoptosis was measured using immunohistochemistry for caspase-3. Inflammation was measured via a multiplex cytokine/chemokine assay. ErbB levels were measured using PCR and Western Blot.

Results

Budesonide co-treatment caused rats to gain significantly less weight than neratinib alone from day 4 of treatment (P = 0.0418). Budesonide (P = 0.027) and colesevelam (P = 0.033) each reduced the amount of days with moderate diarrhea compared to neratinib alone. In the proximal colon, rats treated with neratinib had higher levels of apoptosis compared to controls (P = 0.0035). Budesonide reduced histopathological injury in the proximal (P = 0.0401) and distal colon (P = 0.027) and increased anti-inflammatory IL-4 tissue concentration (ileum; P = 0.0026, colon; P = 0.031) compared to rats treated with neratinib alone. In the distal ileum, while budesonide decreased ErbB1 mRNA expression compared to controls (P = 0.018) (PCR), an increase in total ErbB1 protein was detected (P = 0.0021) (Western Blot).

Conclusion

Both budesonide and colesevelam show potential as effective interventions against neratinib-induced diarrhea.

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Acknowledgements

This research was funded by Puma Biotechnology. Dr Janet Coller, Discipline of Pharmacology, University of Adelaide assisted with interpretation of mass spectrometry data. Dr Hannah Wardill, Discipline of Physiology, University of Adelaide, and Dr Ysabella Van Sebille, Division of Health Sciences, University of South Australia assisted with the animal study.

Funding

This study was funded by Puma Biotechnology Inc.

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Correspondence to Kate R. Secombe.

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Conflict of interest

Kate Secombe, Imogen Ball, Joseph Shirren, Anthony Wignall and John Finnie declare that they have no conflicts of interest. Joanne Bowen has received research funding from Puma Biotechnology, AstraZeneca, Helsinn and Pfizer. Dorothy Keefe is a consultant for and owns stock in Entrinsic Health Solutions. Francesca Avogadri-Connors, Elizabeth Olek, David Martin and Susan Moran were staff of Puma Biotechnology at the time of the study.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Secombe, K.R., Ball, I.A., Shirren, J. et al. Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model. Cancer Chemother Pharmacol 83, 531–543 (2019). https://doi.org/10.1007/s00280-018-3756-8

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  • DOI: https://doi.org/10.1007/s00280-018-3756-8

Keywords

  • Targeted therapies
  • Diarrhea
  • Breast cancer
  • Rat model
  • Neratinib