Abstract #2816: Biologic effects of NVP-BEZ235, an orally available dual PI3K/mTOR inhibitor, in human breast, lung, colon, pancreas, and liver cancer cell lines in vitro.

Background: Signaling via activation of the phosphatidylinositol-3 kinase (PI3K)/ AKT pathway is a major determinant for cell growth and survival. Aberrant activation of this pathway from receptor tyrosine kinase signaling loss of the negative regulator PTEN, and activating mutations in the p110-\#945; subunit have been described in many epithelial malignancies. NVP-BEZ235 is a potent orally available reversible small molecule ATP- competitive inhibitor of PI3K and mTOR. Recent studies ( Maira 2008, Serra 2008) have described NVP-BEZ235 to inhibit the growth of cells with and without activating mutations in PI3K. To identify potential markers of response to guide development; we evaluated its anti-proliferative and cytotoxic effects in several molecularly characterized human cell line panels. Methods: Over 100 human cancer cell lines, including 47 breast, 40 non-small cell lung cancer, 27 colon, 20 pancreas, and 11 liver cancer cell lines were exposed in vitro to NVP-BEZ235 over 12 concentrations in clinically relevant ranges to generate dose response curves. These assays were perfomed over a 6 day incubation using direct cell counts. The ability of NVP-BEZ235 to inhibit proliferation and induce cell death was calculated using IC₅₀ and LD₅₀ values, respectively. PI3K and PTEN mutation status was available from public databases. In addition, baseline gene expression profiles were generated using the Agilent platform. Results: NVP-BEZ235 had potent growth inhibitory effects across all cell line panels with the majority of cell lines, regardless of histology, having IC₅₀ values less than 100 nM. In the breast cancer panel, 10/15 lines with LD₅₀ < 1\#956;M had either PI3k or PTEN mutations. However, in the lung and colon cancer panels, lethality was observed in the absence of these mutations. While potent inhibition was observed in both the pancreas and liver cancer panels, no significant lethality was seen in the clinically relevant concentrations studied. Conclusions: NVP-BEZ235 has potent anti-proliferative effects across several human epithelial malignancies in vitro and induces lethality in a subset. This observation is not limited to cell lines harboring to PI3k and/ or PTEN mutations. Analysis of baseline gene expression profiles for common predictors of response is ongoing.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2816.