Abstract 2629: PIK3CA mutation promotes tumor cell invasion and migration independently from AKT and mTOR kinase in cancer cells.

Abstract

Abstract Although the role of phosphoinositide-3 kinase (PI3K) in promoting tumorigenesis, tumor cell survival, proliferation and metabolism has been extensively evaluated, the mechanisms of other oncogenic processes mediated by PI3K have not been fully addressed. We report here a novel molecular mechanism by which PI3K mediates tumor cell invasion and migration using isogenic cell lines and highly selective PI3K pathway inhibitors. First of all, using a set of MCF10A-derived isogenic cell lines with PIK3CAH1047R, PTEN-deletion, or AKTE17K mutations, we found that activating the PIK3CA mutation, but not PTEN-deletion or AKT mutation, promoted tumor cell migration in a wound healing assay. Treatment of the PIK3CAH1047R isogenic cell line with a highly selective PI3K inhibitor (BAY 80-6946) effectively blocked tumor cell migration. Interestingly, neither allosteric AKT inhibitor nor mTOR kinase inhibitors were able to inhibit PIK3CA-stimulated cell migration although both AKT and mTOR kinase inhibitors potently inhibited AKT phosphorylation in these cells. In contrast, AKT inhibition enhanced the migration of PIK3CA mutant isogenic cells. This result revealed a novel AKT- and mTOR-independent mechanism by which activating PI3K mutation stimulates tumor cell migration. This conclusion was further confirmed in a panel of gastric cancer cell line in both wound healing and migration assays. Additional mechanistic experiments are being performed to examine downstream signaling events and will be presented. Taken together, these data suggest a role of PI3K in contributing to tumour metastasis independent of the canonical PI3K-AKT-mTOR axis and further validation of using AKT inhibitor for the treatment of metastatic PIK3CA mutant tumors to be conducted. Citation Format: Bhaskar Bhattachara, Enrico Stasik, Sarah Low, Andrea Sturz, Christoph Schatz, Richie Soong, Ningshu Liu. PIK3CA mutation promotes tumor cell invasion and migration independently from AKT and mTOR kinase in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2629. doi:10.1158/1538-7445.AM2013-2629