Recent proteomic data have uncovered an interdependence of PI3K (phosphatidylinositol 3-kinase) and STAT3. In PI3K-transformed murine cells, STAT3 is phosphorylated on Y705 and activated in a PI3K-dependent manner, and dominant-negative STAT3 interferes with PI3K-induced oncogenic transformation. Phosphorylation of STAT3 in PI3K-transformed murine cells is mediated by the TEC (tyrosine kinase expressed in hepatocellular carcinoma) kinase BMX (bone marrow tyrosine kinase gene in chromosome X) and observations in glioblastoma stem cells reveal similar critical roles for STAT3 and BMX. These new data document an important role of STAT3 in PI3K-driven oncogenic transformation and mark BMX as a promising therapeutic target that could enhance the effectiveness of PI3K inhibitors.

Significance: The PI3K–TOR and STAT3 signaling pathways represent two distinct regulatory networks. The discovery of a functional link between these pathways is significant for our understanding of PI3K- and STAT3-driven oncogenic mechanisms and identifies the TEC kinase BMX as a new cancer target. Cancer Discovery; 1(6); 481–86. ©2011 AACR.