Abstract 5038: AZD8055 is an effective inhibitor of mTOR kinase signaling and breast cancer growth while relieving feedback inhibition of HER-kinase signaling

Abstract

Abstract The PI3K signaling pathway is often dysregulated in human cancer. mTOR kinase is a component of this pathway that mediates activation of cap-dependent translation, other AGC-kinases and feedback inhibition of upstream components of the pathway. The natural product rapamycin binds to and inhibits the mTOR-containing TORC1, but not the TORC2 complex. Rapamycin-like TORC1 inhibitors have modest clinical activity in renal cell and other cancers, but only marginal activity in glioblastoma, prostate and breast cancers in which PI3K/AKT signaling is often activated. The limited antitumor activity of rapamycin may be due to inefficient inhibition of TORC1, induction of TORC1-dependent feedback, or lack of inhibition of TORC2. Potent mTOR kinase inhibitors could obviate these issues by inhibiting both TORC1 and TORC2 and by preventing induction of phosphorylation of AKT at Serine 473. We have now compared the effects of the specific mTOR kinase inhibitor AZD8055 and rapamycin in breast cancer models with amplified HER2 or mutant p110alpha PI3K. As expected, AZD8055 and rapamycin both inhibit S6K and S6 phosphorylation, but only the former inhibits AKT phosphorylation at Serine 473, which is, instead, induced by rapamycin. Moreover, AZD8055 is a more potent inhibitor of 4EBP-1 phosphorylation, CAP-dependent translation, and D-cyclin expression. Thus, the mTOR kinase inhibitor inhibits mTOR functions more effectively than rapamycin. Whereas both drugs cause tumor cells to undergo autophagy and G1 arrest, only AZD8055 induces significant apoptotic cell death. The more effective inhibition of 4EBP1 phosphorylation, cap-dependent translation and enhancement of apoptosis compared to that caused by rapamycin may be due to more complete inhibition of TORC1 function or to abolition of feedback activation of AKT by AZD8055. As previously established with rapamycin, we now show that AZD8055 causes relief of feedback inhibition of HER kinase signaling in these tumors, resulting in marked induction of both ERK and PI3K signaling. These results suggest that mTOR kinase inhibition with drugs such as AZD8055 can more effectively inhibit TOR activity than rapamycin. They therefore have the potential for increased antitumor activity, but relief of TOR kinase-dependent negative feedback could create a rationale for combination therapy. 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 5038.