On the pathogenesis of mTOR inhibitor-associated stomatitis (mIAS)studies using an organotypic model of the oral mucosa

ObjectivemTOR inhibitor treatment of solid cancers is associated with mTOR inhibitor-associated stomatitis (mIAS) a common, significant, dose-limiting toxicity, with aphthous-like lesions. Our objective was to assess the utility of a new organotypic model in defining mIAS' pathogenesis. Materials and methodsThe effect of everolimus on organotypic human oral mucosa was studied. Sterile specimens were assessed 24 and 48h after exposure to varying concentrations of everolimus. Morphologic changes and measures of apoptosis, proliferation, and levels of six Th1 and Th2 cytokines were studied. ResultsFollowing a 24-h incubation, concentrations of 500ngml(-1) of everolimus resulted in histological changes consistent with epithelial injury, disorganization and pre- or early apoptosis, increased TUNEL-positive staining (P<0.05) and reduced PCNA-positive staining cells (P<0.001) and increased levels of IL-6 (P<0.0001), IL-8 (P<0.01), and IFN- (P<0.09). ConclusionsEverolimus elicited epithelial damage manifest by morphologic changes, increased apoptosis, and decreased proliferation with concurrent release of keratinocyte-derived pro-inflammatory cytokines in the absence of bacteria. The extent of the effect was concentration and time dependent. These results suggest that mIAS is likely initiated by direct epithelial injury, independent of the microbiome. Keratinocyte cytokine release could likely play a role in accelerating an inflammatory infiltrate.