Comparison of dual mTORC1/2 inhibitor AZD8055 and mTORC1 inhibitor rapamycin on the metabolism of breast cancer cells using proton nuclear magnetic resonance spectroscopy metabolomics

Abstract

Dual mTORC1/2 inhibitors may be more effective than mTORC1 inhibitor rapamycin. Nevertheless, their metabolic effects on breast cancer cells have not been reported. We compared the anti-proliferative capacity of rapamycin and a novel mTORC1/2 dual inhibitor (AZD8055) in two breast cancer cell lines (MDA-MB-231 and MDA-MB-453) and analyzed their metabolic effects using proton nuclear magnetic resonance (¹H NMR) spectroscopy-based metabolomics. We found that AZD8055 more strongly inhibited breast cancer cell proliferation than rapamycin. The half-inhibitory concentration of AZD8055 in breast cancer cells was almost one-tenth that of rapamycin. We identified 22 and 23 metabolites from the ¹H NMR spectra of MDA-MB-231 and MDA-MB-453 cells. The patterns of AZD8055- and rapamycin-treated breast cancer cells differed significantly; we then selected the metabolites that contributed to these differences. For inhibiting glycolysis and reducing glucose consumption, AZD8055 was likely to be more potent than rapamycin. For amino acids metabolism, although AZD8055 has a broad effect as rapamycin, their effects in degrees were not exactly the same. AZD8055 and rapamycin displayed cell-specific metabolic effects on breast cancer cells, a finding that deserves further study. These findings help fill the knowledge gap concerning dual mTORC1/2 inhibitors and provide a theoretical basis for their development.

Keywords: AZD8055; Breast cancer; Metabolism; Rapamycin; mTORC1/2.