The PI3K/AKT/mTOR pathway is frequently activated in many human cancers and mTOR has been clinically validated as an effective anti-cancer target by rapamycin analogs such as CCI-779, RAD001 and AP23573. We discovered OSI-027, a potent and selective small molecule mTOR kinase inhibitor that inhibits both mTORC1 and mTORC2 unlike rapamycin and its analogs that inhibit only mTORC1. We profiled several human cancer cell lines to compare the mechanistic and functional effects of rapamycin and OSI-027. Rapamycin completely inhibited phosphorylation of S6 (surrogate for S6K1) and only partially inhibited phosphorylation of 4E-BP1 while OSI-027 completely inhibited phosphorylation of both S6 and 4E-BP1. Furthermore, rapamycin only decreased phosphorylation of AKT (S473) in 13% of cell lines and increased phosphorylation of AKT (S473) in 62% of cell lines after 24h treatment. In contrast, OSI-027 significantly reduced phospho-AKT (S473) in all cell lines tested. OSI-027 showed broad-spectrum anti-proliferative activity against both rapamycin-sensitive and -insensitive cell lines. Rapamycin only induced apoptosis in a small subset of tumor cell lines whereas OSI-027 induced apoptosis in the majority of tumor cell lines tested. These in vitro advantages of OSI-027 relative to rapamycin translated to greater tumor growth inhibition in xenograft models in vivo. These results demonstrate that OSI-027, a dual mTORC1/mTORC2 kinase inhibitor provides superior activity across a broad range of preclinical cancer models compared to rapamycin. Accordingly, OSI-027 has been advanced into Phase I clinical trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4487.