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Germline heterozygous <jats:italic>PTEN<\/jats:italic> gene alterations also underlie <jats:italic>PTEN<\/jats:italic> hamartoma tumour syndrome (PHTS), a rare human cancer\u2010predisposition condition. A key feature of systemic <jats:italic>PTEN<\/jats:italic> deregulation is the inability to adequately dampen PI3\u2010kinase (PI3K)\/mTORC1 signalling. PI3K\/mTORC1 pathway inhibitors such as rapamycin are therefore expected to neutralise the impact of <jats:italic>PTEN<\/jats:italic> loss, rendering this a more druggable context compared with those of other tumour suppressor pathways such as loss of <jats:italic>TP53<\/jats:italic>. However, this has not been explored in cancer prevention in a model of germline cancer predisposition, such as PHTS. Clinical trials of short\u2010term treatment with rapamycin have recently been initiated for PHTS, focusing on cognition and colon polyposis. Here, we administered a low dose of rapamycin from the age of 6\u2009weeks onwards to mice with heterozygous germline <jats:italic>Pten<\/jats:italic> loss, a mouse model that recapitulates most characteristics of human PHTS. Rapamycin was well tolerated and led to a highly significant improvement of survival in both male and female mice. This was accompanied by a delay in, but not full blockade of, the development of a range of proliferative lesions, including gastro\u2010intestinal and thyroid tumours and endometrial hyperplasia, with no impact on mammary and prostate tumours, and no effect on brain overgrowth. Our data indicate that rapamycin may have cancer prevention potential in human PHTS. This might also be the case for sporadic cancers in which genetic PI3K pathway activation is an early event in tumour development, such as endometrial cancer and some breast cancers. To the best of our knowledge, this is the first report of a long\u2010term treatment of a germline cancer predisposition model with a PI3K\/mTOR pathway inhibitor. \u00a9 2022 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6009","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T08:14:55Z","timestamp":1662624895000},"page":"382-394","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Long\u2010term treatment of cancer\u2010prone germline PTEN mutant mice\u00a0with low\u2010dose rapamycin extends lifespan and delays tumour 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