Abstract 1986: Chemosensitivity of a novel Akt inhibitor, MK2206, in gastric cancer cell lines
Authors: Hyosong Kim, Tae Soo Kim, Bo Ram Kwan, Jeong Min Kim, Chan Hee Park Park, Hei-Cheul Jeung, Joong-Bae Ahn, Sang-Joon Shin, Hyun Cheol Chung, Sun Young Rha
Journal: Cancer Research (2011)

Abstract MK2206, a novel phosphatidylinositol-3-kinase (PI3K)/Akt signaling inhibitor is currently being tested in several phase I/II trials for treatment of major human cancers. However, the efficacy of MK2206 in human gastric cancer, which is known to express the increased activation of Akt has not been established. We investigated the antitumor effect of MK2206 and pharmacogenomic gene expression patterns in gastric cancer cells. The antitumor efficacy of MK2206 and taxane (docetaxel/paclitaxel) were examined in 25 gastric cancer cell lines (4 from ATCC, 4 from JCRB, 8 from KCBL, and 9 cell lines established from Korean gastric cancer patients at Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea) using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphnyltetrazolium bromide) assay. Preliminary studies to investigate mechanism of action includes western blot for pAkt/Akt, pErk/Erk and pJNK/JNK. We also performed oligonucleotide microarray analysis with 22K genes to elucidate pharmacogenomic profiles evaluating potential predictive biomarkers for MK2206 activity. After 72 hours after MK2206 exposure, it showed modest chemosensitivity in 25 gastric cancer cell lines with IC50 of the median 1.07 uM (range 0.09-2.12) as a dose-dependent manner. While, the median IC 50 of paclitaxel and docetaxel monotherapy were 0.6 (range &amp;lt;0.001-15.28) and 3.08 (range &amp;lt;0.001-15.06) and they were strongly correlated each other (Spearman correlation, P&amp;lt;0.001). When the expression of Akt by immunoblotting was categorized based on the expression of KATO cell, 72 % of the cells demonstrated higher pAkt expression, whereas most of the cell lines demonstrated pErk expression. Twelve (48%) and 13 cell lines (52%) demonstrated synergistic effect with paclitaxel/MK2206 and docetaxel/MK2206 combinations, retrospectively. In addition, 8 out of 12 (66%) taxol resistant and 8 out of 15 (53.3%) docetaxel resistant gastric cancer cell lines demonstrated synergistic antitumor effect in combining with MK2206. For understanding the mechanism of resistance and selection of biomarker for MK2206, we compared gene expression patterns between 6 MK2206-sensitive and 4 MK2206-resistant cell lines. One hundred fifty one genes related to MK2206 chemosensitivity (by 2-folds, P&amp;lt;0.05) with 65 up-regulated and 49 down-regulated known genes in the resistant cells were identified. Taken together, in gastric cancer cell lines, MK2206 demonstrated the modest antitumor activity and enhances the antitumor activity of taxane even in taxane-resistant cancer cell lines. Further evaluation of efficacy and the downstream signaling pathway in in vivo study is ongoing. This information may be useful to establish response predictive profiles and figure out the underlying action mechanisms of MK2206. 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 1986. doi:10.1158/1538-7445.AM2011-1986