title: On the pathogenesis of mTOR inhibitor-associated stomatitis (mIAS)-studies using an organotypic model of the oral mucosa.
abstract: OBJECTIVE
  mTOR 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.
  
  
  METHODS
  The effect of everolimus on organotypic human oral mucosa was studied. Sterile specimens were assessed 24 and 48 h after exposure to varying concentrations of everolimus. Morphologic changes and measures of apoptosis, proliferation, and levels of six Th1 and Th2 cytokines were studied.
  
  
  RESULTS
  Following a 24-h incubation, concentrations of 500 ng ml-1of 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-γ (P < 0.09).
  
  
  CONCLUSIONS
  Everolimus 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.
authors.affiliation: Biomodels, LLC, Watertown, MA, USA.|Division of Oral Medicine, Brigham and Women's Hospital, Boston, MA, USA.|Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sonis
authors.affiliation: Biomodels, LLC, Watertown, MA, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Andreotta
authors.affiliation: Biomodels, LLC, Watertown, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lyng
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008954:Models, Biological; D009061:Mouth Mucosa / Q000187:drug effects* / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy*; D013280:Stomatitis / Q000139:chemically induced* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D046509:Tissue Culture Techniques
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D016209:Interleukin-8; D007371:Interferon-gamma; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: mTOR inhibitor; organotypic mucosa; pathobiology; stomatitis