Inhibitors of STAT3, β‐catenin, and IGF‐1R sensitize mouse PIK3CA‐mutant breast cancer to PI3K inhibitors

Although mutations in the phosphoinositide 3‐kinase catalytic subunit ( PIK 3 CA ) are common in breast cancer, PI 3K inhibitors alone have shown modest efficacy. We sought to identify additional pathways altered in PIK 3 CA ‐mutant tumors that might be targeted in combination with PI 3K inhibitors. We generated two transgenic mouse models expressing the human PIK 3 CA ‐H1047R‐ and the ‐E545K hotspot‐mutant genes in the mammary gland and evaluated their effects on development and tumor formation. Molecular analysis identified pathways altered in these mutant tumors, which were also targeted in multiple cell lines derived from the PIK 3 CA tumors. Finally, public databases were analyzed to determine whether novel pathways identified in the mouse tumors were altered in human tumors harboring mutant PIK 3 CA . Mutant mice showed increased branching and delayed involution of the mammary gland compared to parental FVB /N mice. Mammary tumors arose in 30% of the MMTV ‐ PIK 3 CA ‐H1047R and in 13% of ‐E545K mice. Compared to MMTV ‐Her‐2 transgenic mouse mammary tumors, H1047R tumors showed increased upregulation of Wnt/β‐catenin/Axin2, hepatocyte growth factor (Hgf)/Stat3, insulin‐like growth factor 2 (Igf‐2), and Igf‐1R pathways. Inhibitors of STAT 3, β‐catenin, and IGF ‐1R sensitized H1047R‐derived mouse tumor cells and PIK 3 CA ‐H1047R overexpressing human HS 578T breast cancer cells to the cytotoxic effects of PI 3K inhibitors. Analysis of The Cancer Genome Atlas database showed that, unlike primary PIK 3 CA ‐wild‐type and HER ‐2 + breast carcinomas, PIK 3 CA ‐mutant tumors display increased expression of AXIN 2, HGF , STAT 3, IGF ‐1, and IGF ‐2 mRNA and activation of AKT , IGF 1‐ MTOR , and WNT canonical signaling pathways. Drugs targeting additional pathways that are altered in PIK 3 CA ‐mutant tumors may improve treatment regimens using PI 3K inhibitors alone.