Abstract 4399: In vitro and in vivo evaluations of correlation between the activation status of signaling pathways and the efficacy of anticancer compounds in a panel of JFCR39 human cancer cell lines

Abstract

Abstract The phosphoinositide 3-kinase (PI3K) pathway and the Ras/mitogen-activated protein kinase (MAPK) pathway are frequently activated in cancer. Activation of these pathways contribute to cell survival, cell cycle progression and cell growth in the tumor, and are expected to influence the efficacy of antitumor compounds including conventional antitumor drugs, PI3K pathway inhibitors and Ras/MAPK pathway inhibitors. However, it is not well understood whether the efficacies of anticancer compounds can be predicted based on these aberrations and on the activation status of signaling pathway members. To clarify this issue, we first examined the mutation, expression and phosphorylation status of PI3K and Ras/MAPK pathway members in a panel of 39 pharmacologically well-characterized human cancer cell lines (JFCR39). Second, we evaluated the in vitro efficacy of various anticancer compounds including PI3K and Ras/MAPK pathway inhibitors and conventional anticancer drugs, combining these data to construct an integrated database of pathway activation status and drug efficacies (JFCR39-DB). In silico analysis of JFCR39-DB enabled us to evaluate correlations between the status of pathway members and the drug efficacies in vitro. For example, KRAS/BRAF mutation prominently correlated with the efficacy of a MEK inhibitor and the inefficacy of PI3K inhibitors, respectively, while phosphorylation levels of Akt correlated with the efficacy of PI3K inhibitors. Some of these correlations were confirmed in human tumor xenografts in vivo, consistent with their ability to serve as predictive biomarkers. Our findings show that JFCR39-DB is a useful tool to identify predictive biomarkers and to study molecular pharmacology of the PI3K and Ras/MAPK pathways in cancer therapy. 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 4399. doi:10.1158/1538-7445.AM2011-4399