Abstract 1965: Antitumor activity of novel Akt inhibitor, perifosine in gastric cancer cell lines (2011)

Abstract Perifosine, a novel phosphatidylinositol-3-kinase (PI3K)/Akt signaling inhibitor is currently being tested in several phase II/III trials for treatment of major human cancers. However, the efficacy of perifosine in human gastric cancer has not been established. As Akt is known to be highly activated in gastric cancer, we investigated the antitumor effect and gene expression patterns of perifosine on gastric cancer cells. The antitumor efficacy of perifosine 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 the Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul, Korea) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphnyltetrazolium bromide) assay. Preliminary studies to investigate mechanism of action include western blot for pAkt/Akt, pErk/Erk and pJNK/JNK. We also performed 22K oligonucleotide microarray analysis to elucidate pharmacogenomic profiles evaluating potential predictive biomarkers for perifosine. After 72 hours after perifosine exposure, it showed the modest chemosensitivity in 25 gastric cancer cell lines with IC50 of median 1.09 uM (range 0.18-9.34) as a dose-dependent manner. The median IC 50 of paclitaxel and docetaxel monotherapy were 0.6 (range &lt;0.001-15.28) and 3.08 (range &lt;0.001-15.06) and they were strongly correlated each other (Spearman correlation, P&lt;0.001). When the expression of pAkt 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. Based on the pAkt expression level, cell lines with higher Akt expression demonstrated more sensitive to perifosine (P=0.003. median 0.6 vs 1.35). When we evaluated the antitumor activity of perifosine in combination with taxane, 10 (40%) and 11 cell lines (44%) showed synergistic effect with paclitaxel/perifosine and docetaxel/perifosine combinations, retrospectively. In addition, 6 out of 10 taxol resistant and 5 out of 10 docetaxel resistant gastric cancer cell lines demonstrated synergistic antitumor effect. Then, we compared gene expression patterns between 6 perifosine-sensitive and 3 perifosine-resistant cell lines and identified 122 genes related to perifosine sensitivity (by 4-folds, P&lt;0.05) including 49 up-regulated and 48 down-regulated known genes in the resistant cells. Taken together, in gastric cancer cell lines, perifosine demonstrated antitumor activity and enhances the antitumor activity of taxane even in taxane-resistant cancer cell lines. Further evaluation of in vivo efficacy and downstream signaling pathway is ongoing. Current data may be useful to establish response predictive profiles and figure out the underlying action mechanisms of perifosine. 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 1965. doi:10.1158/1538-7445.AM2011-1965