Potentiation of calcium ‐activated chloride secretion and barrier dysfunction may underlie EGF receptor tyrosine kinase inhibitor‐induced diarrhea

Tyrosine kinase inhibitors directed to the receptor for epidermal growth factor (EGFr TKIs) reverse the inhibitory effect of EGF on calcium ‐dependent chloride secretion across intestinal epithelial cells and potentiate secretory responses to carbachol (CCh). In addition, these drugs have a deleterious effect on barrier function. These effects likely contribute synergistically to the ability of EGFr TKIs to induce diarrhea. CCh activa ted ERK phosphorylation in a manner that was relatively insensitive to EGFr TKIs and delayed the deleterious effects of the drugs on barrier function. CaCC, calcium‐dependent chloride ion channel; CFTR, cystic fibrosis transmembrane conductance regulator; m3R, M3 muscarinic acetylcholine receptor; ERK, extracellular signal regulated kinase. AbstractEpidermal growth factor receptor tyrosine kinase inhibitors (EGFr TKIs) are first ‐line therapies for various cancers, and cause dose‐limiting severe diarrhea in many patients. We hypothesized that diarrhea caused by EGFr TKIs might reflect actions on epithelial transport, barrier function, or both, which we tested using cell cultures including murine and human enteroid‐der ived monolayers (EDMs), analyzed using electrophysiological and other relevant methods. EGFr TKIs (such as afatinib, erlotinib, and osimertinib) reversed the acute inhibitory effect of EGF on chloride secretion induced by carbachol (CCh) across T84 human colonic epithelial cells, which correlated wi th the diarrhea‐indu...
Source: Physiological Reports - Category: Physiology Authors: Tags: ORIGINAL RESEARCH Source Type: research