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

Abstract

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.

Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer

“…This is the first study to compare functional in vivo permeability, and morphological assessment of tight junction proteins in the setting of dacomitinib‐induced gut toxicity. Our previous research has indicated that dacomitinib induces severe ileal damage and barrier dysfunction . This study further characterized this barrier dysfunction; showing increases in barrier permeability to 4 kDa FITC‐dextran, and clear changes to tight junction proteins.…”

“…FITC dextran was administered orally to measure gastrointestinal permeability. Serum FITC dextran levels were significantly elevated in rats of either treatment arm involving dacomitinib . Rats treated with dacomitinib alone had significantly elevated levels of serum FITC dextran compared with controls ( p = 0.0018), and crofelemer alone ( p = 0.0043).…”

“…). At Day 21, the control group had on average gained 46.38 ± 2.459%, the crofelemer group gained 39.27 ± 8.298%, the dacomitinib group gained 18.99 ± 5.602%, and the crofelemer/dacomitinib combination group gained 13.36 ± 6.846% body weight compared with Day 1 of treatment.…”

“…Approximately 50% of rats treated with combination crofelemer and dacomitinib had severe diarrhea (grade 3: severe diarrhea as watery stools ± mucous with fur staining incorporating hind legs). Approximately 30% of rats treated with dacomitinib alone had severe diarrhea . Rats treated with dacomitinib/crofelemer combination had significantly worse diarrhea than rats treated with dacomitinib alone ( p = 0.0003).…”

“…Following the results seen in vitro, which showed dacomitinib increased chloride secretion and crofelemer inhibited it, treatment was then translated into an animal model. Our previous publication presents data of control and dacomitinib alone treated rats . Rats treated with vehicle control did not develop diarrhea at any time point .…”