Journal Article

PI3K-targeting strategy using alpelisib to enhance the antitumor effect of paclitaxel in human gastric cancer

Kui Jin Kim, Jong Seok Lee, Jee Hyun Kim, Soo Mee Bang, Jeong Ok Lee, Ji Won Kim, Hark Kyun Kim, Yu Jung Kim, Jin Won Kim, Ji Hea Sung, Koung Jin Suh, Ji Yun Lee, Se Hyun Kim, Keun Wook Lee

2020

Overview

PIK3CA mutations are frequently observed in various human cancers including gastric cancer (GC). This study was conducted to investigate the anti-tumor effects of alpelisib, a PI3K p110α-specific inhibitor, using preclinical models of GC. In addition, the combined effects of alpelisib and paclitaxel on GC were evaluated. Among the SNU1, SNU16, SNU484, SNU601, SNU638, SNU668, AGS, and MKN1 GC cells, three PIK3CA -mutant cells were predominantly sensitive to alpelisib. Alpelisib monotherapy decreased AKT and S6K1 phosphorylation and induced G 0 /G 1 phase arrest regardless of PIK3CA mutational status. The alpelisib and paclitaxel combination demonstrated synergistic anti-proliferative effects, preferentially on PIK3CA -mutant cells, resulting in increased DNA damage response and apoptosis. In addition, alpelisib and paclitaxel combination potentiated anti-migratory activity in PIK3CA- mutant cells. Alpelisib partially reversed epithelial–mesenchymal transition markers in PIK3CA -mutant cells. In a xenograft model of MKN1 cells, the alpelisib and paclitaxel combination significantly enhanced anti-tumor activity by decreasing Ki-67 expression and increasing apoptosis. Moreover, this combination tended to prolong the survival of tumor-bearing mice. Our data suggest promising anti-tumor efficacy of alpelisib alone or in combination with paclitaxel in PIK3CA -mutant GC cells.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 631/67 / 692/4017 / 692/4028/67 / AKT protein / Animals / Antineoplastic Combined Chemotherapy Protocols / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Antitumor activity / Antitumor agents / Apoptosis / Apoptosis - drug effects / Caspases / Caspases - metabolism / Cell Cycle / Cell Cycle - drug effects / Cell Cycle Checkpoints / Cell Cycle Checkpoints - drug effects / Cell Line, Tumor / Cell Movement / Cell Movement - drug effects / Cell Proliferation / Cell Proliferation - drug effects / DNA Damage / Epithelial-Mesenchymal Transition / Epithelial-Mesenchymal Transition - drug effects / Female / G1 phase / Gastric cancer / Humanities and Social Sciences / Humans / Mesenchyme / Mice, Nude / multidisciplinary / Mutants / Mutation / Mutation - genetics / Paclitaxel / Paclitaxel - pharmacology / Paclitaxel - therapeutic use / Phosphatidylinositol 3-Kinases / Phosphatidylinositol 3-Kinases - genetics / Phosphatidylinositol 3-Kinases - metabolism / Phosphoinositide-3 Kinase Inhibitors / Phosphoinositide-3 Kinase Inhibitors - pharmacology / Phosphoinositide-3 Kinase Inhibitors - therapeutic use / Phosphorylation / Science / Science (multidisciplinary) / Stomach Neoplasms / Stomach Neoplasms - drug therapy / Stomach Neoplasms - pathology / Thiazoles / Thiazoles - pharmacology / Thiazoles - therapeutic use / Tumors / Xenograft Model Antitumor Assays / Xenografts