Exploiting an Epigenetic Resistance Mechanism to PI3 Kinase Inhibition in Leukemic Stem Cells

Acquired non-genetic resistance mechanisms to existing therapies contribute to poor outcomes for acute mye-loid leukemia (AML) patients, and inability to target leukemic stem cells (LSCs) can lead to relapse. To over-come these challenges, we tested whether LSCs have dependencies on PI3 kinase (PI3K). We found that LSCs are susceptible to isoform-selective targeting of PI3K and are particularly dependent on the P110 alpha isoform of PI3K. We discovered that PI3K inactivation leads to dynamic changes in EZH2/PRC2 function in leukemic cells, and we uncovered downregulation of EZH2 protein levels as a resistance mechanism in re-sponse to PI3K inhibition. We found that PI3K inhibition in AML cells can lead to compensatory upregula-tion of EZH1, and that EZH1 knockdown can sensitize AML cells to PI3K inhibition. We leveraged this re-sistance mechanism by combining a PI3K inhibitor with an EZH1/2 dual inhibitor, which successfully over-comes the acquired resistance and leads to sustained targeting of AML cells ex vivo and in murine AML and PDX models in vivo. This study identifies a promising novel therapeutic regimen for targeting LSCs in AML.