{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T20:13:20Z","timestamp":1792872800885,"version":"4.5.0"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T00:00:00Z","timestamp":1703203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>It has been 24 years since rapamycin (sirolimus) was approved to mitigate solid organ transplant rejection and 16 years since mTOR (mammalian\/mechanistic target of rapamycin) inhibitors reached patients as a cancer therapy. While the clinical benefits of mTOR inhibitors (mTORi) are robust, so too are their toxicities. Among the most common issues is the development of ulcers of the oral mucosa (mTOR-inhibitor associated stomatitis; mIAS). These lesions are distinct from those of other anti-cancer agents, occur with regularity, and impact patient outcomes. mIAS\u2019 pathogenesis has been the subject of speculation, and its similar presentation to recurrent aphthous stomatitis (RAS) has led to the hypothesis that it might serve as a surrogate to better understand RAS. Based on a review of the literature, the current manuscript provides a hypothesis regarding the mechanisms by which mTORis uniquely initiate mucosal injury and an explanation for the observation that steroids (also an immunosuppressive) are effective in its treatment through a non-immunologic mechanism. Unexplained unique features of mIAS are discussed in this review in the context of future investigation.<\/jats:p>","DOI":"10.3390\/cancers16010068","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T04:44:40Z","timestamp":1703220280000},"page":"68","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A New Hypothesis Describing the Pathogenesis of Oral Mucosal Injury Associated with the Mammalian Target of Rapamycin (mTOR) Inhibitors"],"prefix":"10.3390","volume":"16","author":[{"given":"Stephen T.","family":"Sonis","sequence":"first","affiliation":[{"name":"Divisions of Oral Medicine and Dentistry, Brigham and Women\u2019s Hospital and the Dana-Farber Cancer Institute, Boston, MA 02115, USA"},{"name":"Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02114, USA"},{"name":"Biomodels, LLC, Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1966-6000","authenticated-orcid":false,"given":"Alessandro","family":"Villa","sequence":"additional","affiliation":[{"name":"Oral Medicine, Oral Oncology and Dentistry, Miami Cancer Institute, Miami, FL 33176, USA"},{"name":"Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/2001-1326-1-29","article-title":"Rapamycin and mTOR: A serendipitous discovery and implications in breast cancer","volume":"1","author":"Seto","year":"2012","journal-title":"Clin. 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