Abstract
Abstract Expression of PAK4 (p21-activated serine/threonine kinase 4) is associated with gastric tumorigenesis. Overexpression of PAK4 is correlated with metastasis of gastric cancer and in part confers cisplatin resistance in gastric cancer patients. We transduced the human gastric cancer cell line AGS with CRISPR/cas9 targeting PAK4, and observed reduced cell proliferation and motility. Novel PAK4 allosteric modulators (PAMs) were evaluated for their potential therapeutic use for gastric cancer. A panel of human gastric cancer cell lines was screened with four PAMs (KPT-7189, -7349, -7657, -8752). MTS assay showed inhibition of cell viability by PAMs in 6 of 10 gastric cancer cell lines (IC50 ranged from 50 to 5000 nM). Cell cycle analysis and annexin V assay indicated a combination of cell growth arrest at G1 phase and cell apoptosis after treatment with PAMs. Furthermore, PAMs diminished expression levels of PAK4, induced apoptosis-related molecule caspase-3, and suppressed PI3K/Akt and MEK/Erk signaling. Wound assay showed inhibition of cell migration and soft agar assay demonstrated suppression of colony formation for gastric cancer cells treated with PAMs. Mouse xenograft models are currently under investigation. Remarkably, PAMs in combination with cisplatin induced cell death in cisplatin-resistant gastric cancer cells in a synergistic manner. This study demonstrates PAMs have anti-tumor activity against gastric cancer cells and suggests their potential use for the treatment of gastric cancer. Citation Format: Wenwen Chien, Jinfen Xiao, Ling-Wen Ding, Muhammad Ikhsan B. Muzakar, Qiao-Yang Sun, Sigal Gery, William Senapedis, Sharon Shacham, Erkan Baloglu, H. Phillip Koeffler. Novel PAK4 allosteric modulators (PAMs) provide potential therapeutic options in human 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 138. doi:10.1158/1538-7445.AM2015-138
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