Abstract 3478: PI3K suppression by the mTOR inhibitor ridaforolimus and the AKT inhibitor MK-2206 is associated with enhanced anti-tumor activity and hyperglycemia in preclinical models
Authors: Artime Marlene C. , Blackman Samuel , Ebbinghaus Scot , Lee Ray , Bacco Alessandra Di , Gargano Diana , Zhang Theresa , Muniappa Nagaraja , Sandhu Punam , Gitzlaff Gail , Chavez-Eng Cynthia , Watters James , Chenard Melissa , Clark Edwin , Winter Christopher , Haines Brian B. 
Published: February 2011

The PI3K-AKT-mTOR signaling axis is hyperactivated in subsets of many cancers, providing a strong rationale to therapeutically target this pathway. Strategies that target multiple nodes within this pathway may effectively suppress PI3K signaling and prevent inadvertent de-repression (often noted with single PI3K node inhibition) of negative regulatory loops that serve to restrain pathway activity. For example, mTOR inhibitors may in some settings relieve negative regulation of the oncogene AKT. Thus, co-targeting mTOR and AKT may simultaneously suppress PI3K pathway activity and eliminate feedback activation, ultimately leading to greater efficacy. To address these concepts, the mTOR inhibitor ridaforolimus (AP23573, MK-8669) and the allosteric AKT inhibitor MK-2206 were tested alone and in combination in various in vitro and in vivo assays. Combination treatment inhibited proliferation better than either agent alone within large panels of lung (n= 93) and breast (n= 65) cancer cell lines, and correlated with multi-nodal PI3K pathway suppression, as measured by AKT, S6K, and S6RP phosphorylation levels. Within the breast panel, the ER+ subset was particularly responsive to the combination. In vivo, ridaforolimus alone in three lung cancer xenograft models (A549, H2122, and H460) resulted in elevated tumor levels of phosphorylated AKT and its substrate PRAS40, an effect which was abrogated by the addition of MK-2206. The combination also most effectively suppressed cell division (histone H3) and protein translation (S6RP) for a longer duration than either single agent. Ridaforolimus (1 mg/kg) alone had significant anti-tumor activity (%T/C range for the three models 47-61), while MK-2206 alone exhibited a dose-dependent effect (%T/C for 100 mg/kg: 61-83; %T/C for 200 mg/kg: 40-72). Combination therapy resulted in a significant improvement of anti-tumor activity over single agents in 2 of 3 models, achieving %T/C values of 39-48 and 25-38 for the low and high MK-2206 dose combinations, respectively. The highest combination group had a mean body weight loss of 11% compared to 1.5% for vehicle over the three week period. Blood glucose levels were significantly elevated in mice receiving the combination therapy over vehicle or single agents, an effect consistent with profound PI3K pathway blockade. In summary, combination therapy caused profound and sustained inhibition of the PI3K pathway that was associated with increased anti-tumor activity and hyperglycemia in preclinical models.

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 3478.