GSE183818
EZH2 inhibition confers PIK3CA-driven lung tumors enhanced sensitivity to PI3K inhibition
The purpose of this research is to study the mechanism of the synergistic effect combining EZH2 inhibition and PI3K inhibition. In this study, we observed that the PIK3CA-mutant or amplified lung cancer cells were more sensitive to EZH2 inhibition. PIK3CA E545K, the most common mutation in lung cancer, harbored a modest transformation capacity along with p53 loss in lung epithelial cells, and developed adenocarcinoma autochthonously. EZH2 inhibitor synergized with PI3K inhibitor in human cancer cells in vitro and worked together efficiently in vivo. Mechanistically, EZH2 inhibition cooperated with PI3K inhibition to produce a more potent suppression of phospho-AKT downstream of PI3K. Overall design: RNA-sequencing profiles of normal human lung epithelial cells (BEAS-2B) with empty vector, p53 R175H mutation, p53 R175H mutation+PIK3CA E545K and p53 R175H mutation+KRAS G12V were analyzed to study the molecular mechanisms of how PIK3CA E545K mutation induced malignant transformation and why PIK3CA mutated cells were more sensitive to EZH2 inhibition.