Abstract #2817: Ex vivo and in vivo effects of NVP-BEZ235, a dual pan-PI3K / mTOR inhibitor, on insulin signaling and metabolic regulation.

The gene encoding for the catalytic subunit of the phosphatidylinositol-3-kinase (PI3K), p110a (PIK3CA) is the most frequently mutated kinase in cancer. This discovery triggered the development of small molecule anti-PI3K inhibitors, such as NVP-BEZ235 (a dual PI3K/mTOR inhibitor), which is currently in early-stage clinical trials. However, the PI3K / Akt signaling pathway plays not only an important role in promoting cell growth, proliferation and survival but also in regulating glucose homeostasis by directly mediating insulin-stimulated glucose uptake into insulin sensitive tissues, such as muscle and adipose tissues. Therefore, such a target-specific therapy towards the PI3K pathway is susceptible to perturbance of the glucose metabolism. Here, we compare the effects of our dual PI3K / mTOR inhibitor NVP-BEZ235 to several other publicly available PI3K and mTOR inhibitors with similar or distinct inhibitory profiles. Therefore, we analyze their impact on insulin signaling in CHO-IR cells, on functional glucose transport in 3T3-L1 fibroblasts and on glucose homeostasis in animals by applying insulin and glucose tolerance tests. The ex vivo analysis resulted in expected findings such as the PI3K inhibitor induced impairment of glucose uptake with IC50 values that correlate with their inhibition of phospho-Akt. For example, NVP-BEZ235 treatment of fully differentiated 3T3-L1 adipocytes showed a clear inhibition of glucose uptake with IC₅₀= 111± 25 nM, a range that mirrors the IC₅₀ of phospho-Akt inhibition in CHO-IR cells. In contrast to the ex vivo results, we saw striking differences between various PI3K inhibitors to cause insulin resistance in vivo. In particular, continuous treatment of efficacious doses of NVP-BEZ235 did not result in the expected elevation of basal glucose levels. This lack of perturbance of the glucose homeostasis might be attributed to NVP-BEZ235\#8217;s preferable pharmacokinetic properties with a much stronger exposure to the tumor than to insulin-sensitive tissues. Our results demonstrate the feasibility of effectively blocking the PI3K pathway ex vivo and in vivo resulting in tumor growth inhibition with manageable effects on glucose regulation.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2817.