ErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: Chloride secretion as a mechanistic hypothesis

Sebille, Ysabella Z.A. Van; Gibson, Rachel J.; Wardill, Hannah R.; Bowen, Joanne M.

doi:10.1016/j.ctrv.2015.05.011

Cited by 58 publications

(60 citation statements)

References 82 publications

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“…Currently, no antidiarrheal medication used for the treatment of TKI‐induced diarrhea offers a targeted approach due to the lack of understanding of the underlying mechanisms. HER TKI‐induced diarrhea has recently been hypothesized to be caused by ErbB down‐regulation, where blockade leads to excess chloride secretion and thus secretory diarrhea . Therefore, this study first investigated this hypothesis in an in vitro model.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical studies have demonstrated that crofelemer is a safe and tolerable drug, with no adverse effects being reported . Crofelemer is also appealing because it is too large and polarized to be systemically absorbed, limiting any systemic effects including drug interactions and toxicities . Therefore, this study investigated the effect of dacomitinib and crofelemer on chloride secretion in vitro, and then translated the study to a preclinical rat model of dacomitinib‐induced diarrhea.…”

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confidence: 99%

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Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer

Sebille

Gibson

Wardill

et al. 2017

Intl Journal of Cancer

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Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea, which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an antisecretory agent may be an effective intervention. T84 monolayers were treated with 1 µM dacomitinib and 10 µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n = 48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib-induced diarrhea (p = 0.0003), and did not attenuate weight loss (p < 0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti-secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib-induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO-1 and occludin, and internalization of claudin-1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib-induced ileal damage. Crofelemer worsened dacomitinib-induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer

Sebille

Gibson

Wardill

et al. 2017

Intl Journal of Cancer

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“…Preclinical studies using targeted therapies have shown diarrhoea is not correlative with intestinal mucosal damage [15], suggestive of pathogenic mechanisms that differs to traditional cytotoxic cancer treatments. Gaining significant momentum is the hypothesis that HER TKI-induced diarrhoea is a result of excess chloride secretion based on the established role of HERs in regulating ion conductance channels in the colon [16]. Currently, treatment for cancer therapy-induced diarrhoea is limited; coupled with increasing cancer prevalence, it is clear that the need for a fuller understanding of the mechanism(s), and subsequently therapeutic targets will not abate.…”

Section: Mechanismsmentioning

confidence: 99%

Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer

Sebille

Gibson²,

Wardill³

et al. 2016

Current Opinion in Supportive &Amp; Palliative Care

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“…Recent Phase II research has investigated both antibiotic and probiotic prophylactic treatment for dacomitinib‐induced diarrhoea, with no change in diarrhoea reported . It is hypothesised that the development of dacomitinib‐induced diarrhoea differs from conventional chemotherapy‐induced diarrhoea and does not result due to direct cytotoxicity but rather occurs through alternative mechanisms . As such, traditional diarrhoea management may be not targeting the underlying changes for optimal management.…”

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confidence: 99%

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

Sebille

Gibson

Wardill

et al. 2017

Intl Journal of Cancer

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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.

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ErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: Chloride secretion as a mechanistic hypothesis

Cited by 58 publications

References 82 publications

Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer

Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer

Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer

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

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