Journal
CANCER LETTERS
Volume 523, Issue -, Pages 72-81Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.09.017
Keywords
mTOR inhibitor; Ovarian cancer; MDSC
Categories
Funding
- National Natural Science Foundation Regional Innovation and Development [U19A2003]
- Excellent Youth Foundation of the Sichuan Scientific Committee Grant in China [2019JDJQ008]
- Development Program of China [2016YFA0201402]
- National Major Scientific and Technological Special Project for the 'Significant New Drugs Development' [2018ZX09201018-013]
- National Natural Science Foundation of China [81821002]
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High mTORC2 expression level in EOC is associated with poor prognosis, while AZD2014 inhibits tumor growth, reduces peritoneal ascites, and prolongs survival in tumor-bearing mice. In addition, AZD2014 also reduces MDSC accumulation and delays tumor recurrence in EOC models.
Mechanistic target of rapamycin (mTOR) forms two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. Here we investigated the antitumor effect of dual mTORC1/2 inhibitor AZD2014 on epithelial ovarian cancer (EOC) and its potential effect on immunosuppressive myeloid-derived suppressor cells (MDSCs). Immunohistochemical analysis of mTORC1 and mTORC2 was performed on a human ovarian cancer tissue microarray. High mTORC2 expression level was associated with shorter survival in EOC, whereas mTORC1 was not correlate with patients' prognosis. AZD2014 suppressed mTOR signaling pathway in ovarian cancer cells, inhibited proliferation and induced G1-phase cell cycle arrest and apoptosis. In tumor-bearing mice, AZD2014 treatment limited tumor growth, reduced peritoneal ascites, and prolonged survival. AZD2014 specifically reduced MDSCs migration and accumulation in EOC peritoneal fluid but not in the spleen. Moreover, subsequent AZD2014 treatment after cisplatin chemotherapy delayed EOC recurrence. Collectively, we observed that high mTORC2 expression level in EOC indicated a poor prognosis. Remarkably, in tumor-bearing mice, AZD2014 diminished MDSC accumulation and delayed tumor growth and recurrence.
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