Activity Of Bay1082439, A Balanced Pi3k Alpha/Beta Inhibitor, In Gastric Cancer

Background: Activation of the p110α and p110β subunits of PI3K by PIK3CA mutation (7% of cancers), PIK3CA amplification (36-60%) and/or PTEN loss (33-47%) is a frequent oncogenic event in gastric cancer. Here, we report on the activity, mode of action and biomarker analysis of BAY1082439, a balanced PI3Kα/β inhibitor, in cell lines and xenografts from Asian and Caucasian gastric cancer patients. Methods: Twenty cell lines were screened in vitro for the sensitivity to BAY1082439 using cell proliferation, cell cycle, migration and invasion assays. In vivo activity and mode of action of BAY 1082439 were further assessed by pathway inhibition, tumor growth inhibition, and effects on tumor stromal cells. Molecular features were assessed by Oncocarta analysis, gene expression arrays, and immunohistochemistry. Results: Seven cell lines were sensitive to BAY1082439, which included 6/7 cell lines with PIK3CA mutations and/or PTEN loss. In vivo study with 15 PDX and 2 cell line models revealed that tumors with genetic alteration of PIK3CA and PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression were more sensitive to BAY 1082439 (tumor growth inhibition u003e90%), while tumors harboring KRAS mutation and/or overexpressing EGFR were insensitive or less responsive to BAY 1082439. Interestingly, BAY1082439 did not inhibit proliferation of MKN45 cells in-vitro (IC50u003e10μM), however it induced tumor stasis in this highly vascularized MKN45 xenografts. The anti-angiogenic activity BAY 1082439 was also demonstrated in patient derived gastric cancer models assessed by CD31 immunohistochemistry. BAY1082439 was also active in many tumors resistant to standard-of-care chemotherapy. Synergistic or additive effects on tumor growth and apoptosis were observed for BAY1082439 in combination with paclitaxel, 5-FU, and capecitabine/oxaliplatin. Conclusions: The PI3Kα/β balanced inhibitor BAY1082439 showed considerable anti-tumor activity including tumor regression in gastric cancer models with genetic alteration or activation of PI3Kα/β and/or PI3Kα/β as single agent or in combination. Citation Format: Huynh T. Hung, Richard Ong, Katja Haike, Elissaveta Petrova, Mei Ling Chong, Marie Loh, Bhaskar Bhattacharya, Richie Soong, Ningshu Liu. Activity of BAY1082439, a balanced PI3Kα/β inhibitor, in gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2674. doi:10.1158/1538-7445.AM2015-2674