The PI3K/AKT/mTOR pathway is frequently activated in human cancers and mTOR is a clinically validated target for therapeutic intervention in this pathway. We have discovered OXA-01, a potent and selective small molecule mTOR kinase inhibitor that inhibits both mTORC1 and mTORC2, unlike rapamycin and its analogs that directly inhibit only mTORC1. We have used a panel of ~50 cell lines to determine the impact of mTORC1 inhibition by rapamycin vs. both mTORC1 and mTORC2 inhibition by OXA-01 on p4E-BP1 (T37/46), pS6, pAKT (S473), cell proliferation and apoptosis. Rapamycin completely inhibited pS6 (surrogate for S6K1) and only partially inhibited phosphorylation of 4E-BP1. OXA-01 completely inhibited phosphorylation of both S6 and 4E-BP1. Rapamycin inhibited pAKT (S473) only in ~ 20% of cell lines, but induced pAKT (S473) in ~ 60% of cell lines after 24h treatment. In contrast, OXA-01 universally inhibited pAKT (S473) in all of the cell lines tested. The anti-proliferative effects of rapamycin also varied among cell lines. In a given tumor type, ~50% of cell lines were insensitive to rapamycin. On the other hand, OXA-01 showed broad-spectrum anti-proliferative activity in both rapamycin-sensitive and insensitive cell lines. Rapamycin only induced apoptosis in the small subset of tumor cell lines in which it inhibited pAKT, whereas OXA-01 inhibited pAKT and induced apoptosis in the majority of tumor cell lines. These in vitro advantages of OXA-01 relative to rapamycin translated to greater tumor growth inhibition in xenograft models. These results demonstrate that a dual mTORC1/mTORC2 kinase inhibitor induces greater inhibition of cell proliferation and apoptosis than rapamycin in a wide range of cell types which results in superior anti-tumor efficacy of a dual mTORC1/mTORC2 kinase inhibitor, OXA-01 over rapamycin in tumor xenograft models

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3711.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO