Abstract 4496: INK128, an orally active TORC1/2 kinase inhibitor, shows broad antitumor activity and enhances efficacy of cytotoxic as well as targeted agents

mTOR kinase operates via two distinct multi-protein complexes, TORC1 and TORC2, which together regulate growth, metabolism, angiogenesis and survival. Because the PI3K/Akt/mTOR pathway integrates nutrient and hormonal signaling and is frequently dysregulated in human cancer, the mTOR kinase has become an important target for oncology drug development. However, multiple genomic and signaling pathways are often simultaneously activated in cancer, and pathway redundancy and compensatory feedback can blunt the activity of even the most potent anticancer agents. Thus, it is important to study the anti-tumor efficacy of potential anticancer agents, both alone and in combination with cytotoxic and targeted agents, to achieve the optimal therapeutic effect. Through rational drug design we have discovered INK128, a potent and selective TORC1/2 inhibitor with outstanding drug-like properties. INK128 inhibits both the phosphorylation of S6 and 4EBP1, downstream substrates of TORC1, and selectively inhibits AKT phosphorylation at Ser473, the downstream substrate of TORC2, both in vitro and in vivo. Potent inhibition was also observed in cell lines resistant to rapamycin and PanPI3K inhibitors. Daily, oral administration of INK128 inhibited angiogenesis and tumor growth in multiple xenograft models with predicted PK/PD relationship. We have studied INK128 in combination with chemotherapeutic agents as well as with molecular targeted agents both in vitro and in vivo tumor models. In most cases, INK128 demonstrated a synergistically enhanced inhibition of tumor growth and suppression of respective signaling pathways. Additionally, induction of apoptosis was observed only when INK128 was used in combination, suggesting apoptosis as a potential contributor to the observed synergy. A subset of the agents that displayed synergy when combined with INK128 in vitro were evaluated in a number of xenograft models. The combinations were well-tolerated and displayed both enhanced anti-tumor efficacy and enhanced inhibition of key pharmacodynamic markers. In summary, INK128 offers a compelling approach to the treatment of cancer either as a single agent or in combination with other anti-cancer agents. 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 4496.