Li-Fraumeni syndrome (LFS) is a classic cancer predisposition disorder commonly associated with germline mutations of the <i>TP53</i> tumor suppressor gene. <i>TP53 </i>mutation carriers are at risk to develop a wide spectrum of early onset cancers with a 75% lifetime risk in males and 93% in females. Interestingly, evidence shows that inhibition of the mTOR signal transduction pathway delays or eliminates tumour onset and increases lifespan in a murine model of p53 deficiency. The mechanism for this mTOR-mediated increase in lifespan is currently unknown. In this study, we test the hypothesis that mTOR inhibition increases lifespan of individuals that are predisposed to cancer by positively influencing the DNA damage response (DDR), hence decreasing the rate of the secondary spontaneous mutations responsible for the malignant transformation. To explore this possibility, we make single cell measurements on fibroblasts derived from LFS patients, and measure the correlation of DDR and mTOR activity with MATLAB analytics. Our preliminary data show that the two processes, DDR and mTOR activation, are indeed mutually influencing each other on a single cell basis. These results suggest that pharmacological inhibitors of the mTOR pathway may serve as a preventative intervention in individuals with cancer predisposition such as LFS.

mTOR inhibition increases lifespan in Li-Fraumeni Syndrome fibroblasts by positively influencing the DNA damage response

255th National Meeting (2018)

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