Abstract
Abstract NVP-BKM120 is a pan class I PI3K inhibitor that has recently entered phase II clinical trials. The compound was shown to inhibit cell proliferation and survival of cancer models displaying PI3K pathway dependency, in a dose-dependent manner, and proportionally to the extent of pathway inhibition. To further characterize NVP-BKM120, we have investigated its mechanism of action across a broad range of relevant models and concentrations of the molecule and compared it to other PI3K inhibitors (e.g. GDC0941 and ZSTK474). The effects observed on phenotypical read-outs were similar for all compounds, when tested up to concentrations necessary to achieve near complete pathway inhibition (IC90 for Akt-S473P). More profound effects were however observed with NVP-BKM120, at higher concentrations (>2 micromolar), in PI3K-independent models, suggesting that at these dose levels, NVP-BKM120 might display inhibitory activities other than PI3K. In order to determine this potential off-target activity, a gene expression profiling study was performed in a PI3K insensitive model, comparing effects of GDC0941 and NVP-BKM120 at equipotent concentrations. Gene-Set Enrichment Analysis (GSEA) revealed that NVP-BKM120 at the highest dose only (3.6 micromolar, 2 fold above the S473-Akt IC90 of PI3K sensitive models), led to increased expression of genes involved in G2 and mitotic (M) phases. Subsequent FACS analysis showed that in contrast to the other pan-PI3K inhibitors, NVP-BKM120 was indeed able to induce a strong G2/M arrest in several PI3K non addicted cell lines when used at concentrations higher than 2 micromolar. DAPI and tubulin immuno-histochemistry studies showed that the NVP-BKM120 induced block was phenotypically similar to that of Nocodazole, suggesting effects on spindle dynamics in prometaphase. Indeed, in cellular or in in vitro purified systems, NVP-BKM120 greatly reduced microtubule polymerization.Based on analysis the antitumor activity observed in vivo in PI3K-dependent animal models, it appears that efficacy is solely due to pure PI3K inhibition, as these off-target activities are generally observed at concentrations (corrected for free fraction) that could not be achieved in animals. Based on modeling of human PK data, a similar conclusion can be reached for patients, as the exposure currently observed in plasma does predict sole coverage of PI3K inhibitory activities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4466. doi:10.1158/1538-7445.AM2011-4466
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