Dacomitinib‐induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats

• Published in: International journal of cancer Vol. 140; no. 12; pp. 2820 - 2829
• Main Authors: Van Sebille, Ysabella Z.A., Gibson, Rachel J., Wardill, Hannah R., Secombe, Kate R., Ball, Imogen A., Keefe, Dorothy M.K., Finnie, John W., Bowen, Joanne M.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15-06-2017
• Subjects: Animals; Cancer; Cell Line, Tumor; Cell Survival - drug effects; Cell viability; Chemokine CCL2 - metabolism; Colon; Colorectal Neoplasms - pathology; Cytokines; dacomitinib; Damage localization; Dextran; Diarrhea; Diarrhea - chemically induced; Diarrhea - physiopathology; diarrhoea; Disease Models, Animal; Disruption; Enzyme inhibitors; ErbB; ErbB protein; ErbB-1 protein; ErbB-2 protein; Gastrointestinal tract; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - metabolism; Gastrointestinal Tract - physiopathology; Gene Expression - drug effects; Histology; Humans; Ileum; Ileum - drug effects; Ileum - metabolism; Ileum - physiopathology; Immunohistochemistry; Male; Medical research; mucositis; Permeability; Permeability - drug effects; Protein-tyrosine kinase; Quinazolinones - pharmacology; Quinazolinones - toxicity; Radioimmunoprecipitation Assay; Rats, Wistar; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Serum levels; TKI; mucositis; TKI; ErbB; diarrhoea; dacomitinib
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30699

Dacomitinib—an irreversible pan‐ErbB tyrosine kinase inhibitor (TKI)—causes diarrhoea in 75% of patients. Dacomitinib‐induced diarrhoea has not previously been investigated and the mechanisms remain poorly understood. The present study aimed to develop an in‐vitro and in‐vivo model of dacomitinib‐induced diarrhoea to investigate underlying mechanisms. T84 cells were treated with 1‐4 μM dacomitinib and resistance and viability were measured using transepithelial electrical resistance (TEER) and XTT assays. Rats were treated with 7.5 mg/kg dacomitinib daily via oral gavage for 7 or 21 days (n = 6/group). Weights, and diarrhoea incidence were recorded daily. Rats were administered FITC‐dextran 2 hr before cull, and serum levels of FITC‐dextran were measured and serum biochemistry analysis was conducted. Detailed histopathological analysis was conducted throughout the gastrointestinal tract. Gastrointestinal expression of ErbB1, ErbB2 and ErbB4 was analysed using RT‐PCR. The ileum and the colon were analysed using multiplex for expression of various cytokines. T84 cells treated with dacomitinib showed no alteration in TEER or cell viability. Rats treated with dacomitinib developed severe diarrhoea, and had significantly lower weight gain. Further, dacomitinib treatment led to severe histopathological injury localised to the ileum. This damage coincided with increased levels of MCP1 in the ileum, and preferential expression of ErbB1 in this region compared to all other regions. This study showed dacomitinib induces severe ileal damage accompanied by increased MCP1 expression, and gastrointestinal permeability in rats. The histological changes were most pronounced in the ileum, which was also the region with the highest relative expression of ErbB1.
What's new?
Dacomitinib can hunt down and kill tumor cells that resist other chemotherapy drugs. But the same receptor family that dacomitinib seizes in tumor cells—the ErbB family—also adorn healthy gastrointestinal epithelial cells, causing most patients to suffer from dacomitinib‐induced diarrhea. These authors sought to understand the mechanism behind this, in hopes of managing it. In rats, they observed that dacomitinib caused severe injury to the ileum, which is the region with the highest ErbB1 expression, and gastrointestinal permeability. Inflammation by monocyte infiltration also seems likely to contribute to the damage, since they observed increased MCP‐1 in the ileum.