Targeting PI3Kgamma dependency in leukemia treatment [cytarabine persistence]
Phosphoinositide 3-kinase gamma (PI3K?) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3K? are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3K? complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3K? that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 as a noncanonical substrate of PI3K? that mediates this cell-intrinsic dependency independently of AKT. PI3K? inhibition dephosphorylates PAK1, activates a transcriptional network of NF?B-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3K? inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3K? signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development. Overall design: To investigate the differentially expressed genes between cytarabine-persistent leukemia cells and untreated cells.