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

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

doi:10.1097/spc.0000000000000210

Cited by 6 publications

(14 citation statements)

References 40 publications

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“…Dacomitinib is an emerging small molecule TKI for the treatment of NSCLC, with clinical trials showing diarrhoea as an adverse event in over 78% of patients. 8 The mechanisms of ErbB TKI-induced diarrhoea are unclear with conflicting hypotheses presented in the literature. 9 The present study found dacomitinib does not cause direct cytotoxicity to T84 epithelial cells, supporting the study hypothesis, and previous literature suggesting that ErbB TKI induced-diarrhoea is not due to direct cell death.…”

Section: Discussionmentioning

confidence: 99%

“…8 Severe diarrhoea commonly results in dose reductions and patient withdrawal from clinical trials. 8 Of particular clinical importance is dacomitinib is delivered in a continuous manner over many months; therefore, to optimise dacomitinib therapy, adequate management or prevention of chronic diarrhoea is essential to minimise the impact on the patient's quality of life, increase safety and the ability to complete the course of therapy. Currently management for dacomitinib-induced diarrhoea follows that used in conventional chemotherapy (daily loperamide), however the mechanisms underlying this diarrhoea are likely different.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…This effectively inhibits phosphorylation of the receptor and therefore inhibits downstream signaling . The most commonly reported adverse event associated with dacomitinib therapy has been diarrhea, with an incidence of around 73% . Although less common, severe diarrhea can result in dose reductions (28%), treatment interruptions (12%) and treatment discontinuation (8%) from clinical trials .…”

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confidence: 99%

“…2 The most commonly reported adverse event associated with dacomitinib therapy has been diarrhea, with an incidence of around 73%. 3 Although less common, severe diarrhea can result in dose reductions (28%), treatment interruptions (12%) and treatment discontinuation (8%) from clinical trials. 4 Of particular clinical importance, dacomitinib is delivered in a continuous manner over many months, meaning diarrhea is often prolonged, and as such, impacts significantly on quality of life.…”

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confidence: 99%

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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“…(30-33)This year, Van Sebille and coinvestigators detail the specific gastrointestinal toxicities of first and second generation small molecule tyrosine kinase inhibitors with a focus on non-small cell lung cancer. (34)…”

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Advances in understanding and improving gastrointestinal symptoms during supportive and palliative care

Ciorba

2016

Current Opinion in Supportive &Amp; Palliative Care

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

Cited by 6 publications

References 40 publications

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

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

Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer

Advances in understanding and improving gastrointestinal symptoms during supportive and palliative care

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