Journal Article

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

Keefe, Dorothy, Avogadri-Connors, Francesca, Olek, Elizabeth, Shirren, Joseph, Wignall, Anthony D, Bowen, Joanne M, Ball, Imogen A, Martin, David, Secombe, Kate R, Moran, Susan, Finnie, John

2019

Overview

PurposeNeratinib 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.MethodsRats 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.ResultsBudesonide 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).ConclusionBoth budesonide and colesevelam show potential as effective interventions against neratinib-induced diarrhea.

• Publisher: Springer Nature B.V
• Subject: Apoptosis / Body weight / Breast cancer / Budesonide / Caspase / Caspase-3 / Colon / Diarrhea / Enzyme inhibitors / ErbB protein / ErbB-1 protein / ErbB-2 protein / Gene expression / Ileum / Immunohistochemistry / Inflammation / Interleukin 4 / Intestine / Protein-tyrosine kinase / Rodents