Title: 1827 - Targeting Cancer Stem Cells by mTOR Inhibition in Mucoepidermoid Carcinoma
Nathalia Andrade (Presenter)
University of Sao Paulo
Fabio Nunes, University of Sao Paulo
Jacques Nör, University of Michigan
Objectives: Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor. We have recently reported that cancer stem cells drive the tumorigenic process of MEC. Our objective was to investigate the effect of mTOR inhibition in the pathobiology of cancer stem cells in MEC.
Methods: We performed immunohistochemistry for p-mTOR/p-S6K-1 in an annotated panel of human MEC and correlated results to patient outcomes, and performed co-immunoflorescence for ALDH/p-mTOR in human MEC. Mechanistic studies were performed in 3 human MEC cell lines with inhibitors of the mTOR signaling pathway. We performed cytotoxic, western blot, flow cytometry for ALDH/CD44, salispheres and apoptosis assays. In addition, we performed genetic silencing of mTOR, and in vivo assays with chemical and genetic mTOR inhibitors.
Results: We observed that mTOR pathway is constitutively active in MEC cancer stem cells, and that high mTOR expression correlates with poor patient prognosis (p=0.002941). mTOR inhibition led to loss of self-renewal and decrease fraction of cancer stem cells in vitro (p<0.05) and in vivo (p=0.0027). A decrease in p-AKT upon mTOR inhibition indicated involvement of mTORC2. mTOR inhibition with Temsirolimus caused MEC tumor regression in vivo (p < 0.0001) and mTOR silencing (shRNA) caused slowdown of tumor growth over 90 day follow-up (p<0.0001).
Conclusions: Collectively, these results demonstrated that mTOR signaling is required for the survival of MEC cancer stem cells, and suggested that patients with mucoepidermoid carcinoma might benefit from therapeutic inhibition of mTOR.
This abstract is based on research that was funded entirely or partially by an outside source:
R01-DE23220, R01-DE21139 from the NIH/NIDCR (JEN) and 99999.006524/2015-00 from CAPES (NPA)
The submitter must disclose the names of the organizations with which any author have a relationship, the nature of the relationship, and the clinical or research area involved. The following is submitted: NONE