Abstract 4488: INK128: An orally active TORC1/2 kinase inhibitor demonstrates potent antitumor activity in preclinical models of renal cell carcinoma

Abstract

Abstract Anti-angiogenic agents have demonstrated promising activity in patients with renal cell carcinoma (RCC). Patients with clear cell RCC often have mutations or silencing of the von Hippel-Lindau gene, leading to an accumulation of HIF 1 alpha (HIF1α), a key mediator of hypoxia-triggered neo-angiogenesis. The mammalian target of rapamycin (mTOR) is upstream of HIF1a and downstream of the VEGF pathway. mTOR kinase comprises two distinct multi-protein complexes, TORC1 and TORC2, which together regulate growth, metabolism, angiogenesis and survival. Pharmaceutical derivatives of rapamycin, a partial allosteric inhibitor of TORC1, provide clinical proof of concept for targeting mTOR in RCC as well as insights into how ATP-competitive TORC1/2 inhibitors might provide superior efficacy. Through rational drug design we have discovered INK128, a potent, selective TORC1/2 inhibitor with outstanding drug-like properties. We investigated INK128 in preclinical in vitro and in vivo models of RCC. Interestingly, while both INK128 and rapamycin exhibit comparable anti-angiogenic activity in vitro, INK128 correlated with potent and complete blockade of cell proliferation, while rapamycin failed to establish a dose-dependent maximum inhibition of tumor cell proliferation. A comparison of INK128, rapamycin, Nexavar and Avastin demonstrated that all exhibited potent inhibition of tumor growth, via different molecular mechanisms. INK128 inhibits phosphorylation of AKT, S6 and 4EBP1; rapamycin inhibits only S6 phosphorylation and induces AKT phosphorylation; Nexavar and Avastin have little effect on the PI3K/AKT/mTOR pathway. Only INK128 induced autophagy and decreased expression of cyclin D1. INK128 and rapamycin both inhibit expression of HIF-1α and VEGF, which contributes to their anti-angiogenic activity. We conclude that, although Nexavar, Avastin and rapamycin exert their activity primarily through effects on the tumor microenvironment, the anti-tumor activity of INK128 is derived from direct inhibition of tumor cell growth as well as anti-angiogenic activities. In summary, targeting TORC1/2 signaling with INK128 offers a compelling approach to the treatment of RCC. 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 4488.