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The GLP-2 analogue elsiglutide reduces diarrhoea caused by the tyrosine kinase inhibitor lapatinib in rats

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Abstract

Purpose

Lapatinib is a small molecule tyrosine kinase inhibitor used to treat breast cancer, often in combination with chemotherapy. Diarrhoea commonly occurs in up to 78% of patients undertaking lapatinib treatment. The mechanism of this diarrhoea is currently unknown. Elsiglutide is a GLP-2 analogue known to increase cell proliferation and reduce apoptosis in the intestine.

Methods

We used a previously developed rat model of lapatinib-induced diarrhoea to determine if co-treatment with elsiglutide was able to reduce diarrhoea caused by lapatinib. Additionally, we analysed the caecal microbiome of these rats to assess changes in the microbiome due to lapatinib.

Results

Rats treated with lapatinib and elsiglutide had less severe diarrhoea than rats treated with lapatinib alone. Serum lapatinib levels, blood biochemistry, myeloperoxidase levels and serum limulus amebocyte lysate levels were not significantly different between groups. Rats treated with lapatinib alone had significantly higher histopathological damage in the ileum than vehicle controls. This increase was not seen in rats also receiving elsiglutide. Rats receiving lapatinib alone had lower microbial diversity than rats who also received elsiglutide.

Conclusions

Elsiglutide was able to reduce diarrhoea from lapatinib treatment. This does not appear to be via reduction in inflammation or barrier permeability, and may be due to thickening of mucosa, leading to increased surface area for fluid absorption in the distal small intestine. Microbial changes seen in this study require further research to fully elucidate their role in the development of diarrhoea.

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Acknowledgements

Funding for this project was provided by Helsinn Healthcare in the form of an unrestricted educational grant. Mr Joseph Shirren and Mrs Imogen Ball provided technical assistance. Dr Hannah Wardill assisted with CLC Genomics Workbench software. Dr Sergio Cantoreggi from Helsinn Healthcare provided assistance in planning the study.

Funding

This study was funded by Helsinn Healthcare Inc. Joanne Bowen has received research funding from Puma Biotechnology, AstraZeneca and Pfizer. Dorothy Keefe is a consultant for and owns stock in Entrinsic Health Solutions. Claudio Pietra is an employee of Helsinn Healthcare Inc.

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Authors and Affiliations

  1. Division of Health Sciences, School of Pharmacy and Medical Sciences, University of South Australia, Level 4, Playford Building, Adelaide, South Australia, 5005, Australia

    Bronwen J. Mayo, Anthony D. Wignall & Daniel Thorpe

  2. Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia

    Kate R. Secombe, Emma Bateman, Dorothy M. Keefe & Joanne M. Bowen

  3. Helsinn Healthcare, Lugano, Switzerland

    Claudio Pietra

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  1. Bronwen J. Mayo
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Correspondence to Bronwen J. Mayo.

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Bronwen Mayo, Kate Secombe, Anthony Wignall, Emma Bateman and Daniel Thorpe declare that they have no conflicts of interest.

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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 (SA Pathology and The University of Adelaide). This article does not contain any studies with human participants performed by any of the authors.

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Mayo, B.J., Secombe, K.R., Wignall, A.D. et al. The GLP-2 analogue elsiglutide reduces diarrhoea caused by the tyrosine kinase inhibitor lapatinib in rats. Cancer Chemother Pharmacol 85, 793–803 (2020). https://doi.org/10.1007/s00280-020-04040-0

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