ArticleJCI insight2019
Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrhea.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- Potassium channels in intestinal epithelial cells and their pharmacological modulation: a systematic review.American journal of physiology. Cell physiology · 2021Pooled it
- Epithelial plasma membrane transporters as drug targets.Physiological reviews · 2026Review
- The natural statin α,β-dehydromonacolin K exerts anti-secretory effect in human intestinal epithelial cells via a nonsense-mediated mRNA decay-dependent mechanism.Pharmaceutical biology · 2025Article
- Progress of personalized medicine of cystic fibrosis in the times of efficient CFTR modulators.Molecular and cellular pediatrics · 2025Review
- Mechanism of Atractylenolide Ⅲ alleviating pyrotinib-induced diarrhea by regulating AMPK/CFTR pathway through metabolite of gut microbiota.Journal of traditional and complementary medicine · 2025Article
- Disruption of epithelium integrity by inflammation-associated fibroblasts through prostaglandin signaling.Science advances · 2024Article
- Review
- Mg2+ supplementation treats secretory diarrhea in mice by activating calcium-sensing receptor in intestinal epithelial cells.The Journal of clinical investigation · 2024Article
- Efficacy, toxicity and prognostic factors of pyrotinib‑involved neoadjuvant therapy in HER2‑positive breast cancer: A retrospective study.Oncology letters · 2023Article
- Chitosan Oligosaccharide Promotes Junction Barrier through Modulation of PI3K/AKT and ERK Signaling Intricate Interplay in T84 Cells.Polymers · 2023Article
- Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study.Investigational new drugs · 2023Observational
- Management of diarrhea induced by EGFR-TKIs in advanced lung adenocarcinoma.Therapeutic advances in medical oncology · 2023Review
- Article
- Intestinal secretory mechanisms and diarrhea.American journal of physiology. Gastrointestinal and liver physiology · 2022Review
- Neratinib causes non-recoverable gut injury and reduces intestinal cytochrome P450 3A enzyme in mice.Toxicology research · 2022Article
- Chloride transport modulators as drug candidates.American journal of physiology. Cell physiology · 2021Review
- Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer.Biology · 2021Article
- Effect of the KCa3.1 blocker, senicapoc, on cerebral edema and cardiovascular function after cardiac arrest - A randomized experimental rat study.Resuscitation plus · 2021Article
- Epidermal growth factor receptor inhibitor-induced diarrhea: clinical incidence, toxicological mechanism, and management.Toxicology research · 2021Review
- Repurposing calcium-sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas.JCI insight · 2021Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Diarrhea is a major side effect of ErbB receptor tyrosine kinase inhibitors (TKIs) in cancer chemotherapy. Here, we show that the primary mechanism of ErbB TKI diarrhea is activation of basolateral membrane potassium (K+) channels and apical membrane chloride (Cl-) channels in intestinal epithelia and demonstrate the efficacy of channel blockers in a rat model of TKI diarrhea. Short-circuit current in colonic epithelial cells showed that the TKIs gefitinib, lapatinib, and afatinib do not affect basal secretion but amplify carbachol-stimulated secretion by 2- to 3-fold. Mechanistic studies with the second-generation TKI afatinib showed that the amplifying effect on Cl- secretion was Ca2+ and cAMP independent, was blocked by CF transmembrane conductance regulator (CFTR) and K+ channel inhibitors, and involved EGFR binding and ERK signaling. Afatinib-amplified activation of basolateral K+ and apical Cl- channels was demonstrated by selective membrane permeabilization, ion substitution, and channel inhibitors. Rats that were administered afatinib orally at 60 mg/kg/day developed diarrhea with increased stool water from approximately 60% to greater than 80%, which was reduced by up to 75% by the K+ channel inhibitors clotrimazole or senicapoc or the CFTR inhibitor (R)-BPO-27. These results indicate a mechanism for TKI diarrhea involving K+ and Cl- channel activation and support the therapeutic efficacy of channel inhibitors.
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