Dataset Information

Targetable leukemia dependency on noncanonical PI3Kγ signaling

ABSTRACT: Phosphoinositide 3-kinase gamma (PI3Kγ) 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 PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ 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 PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 kinase as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ 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 PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Dendritic Cell, Cell Culture

DISEASE(S): Blastic Plasmacytoid Dendritic Cell Neoplasm

SUBMITTER: Miguel Prado

LAB HEAD: Miguel A. Prado

PROVIDER: PXD045702 | Pride | 2024-03-19

REPOSITORIES: Pride

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	552326_a26410_AL_TMT01_03_TrypLysC_2MC_2mods_MetOx_IAA_TMTpro_20ppm_0.02.mzIdentML	Mzid
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	552328_a26412_AL_TMT01_05_TrypLysC_2MC_2mods_MetOx_IAA_TMTpro_20ppm_0.02.mzIdentML	Mzid

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Publications

Targetable leukaemia dependency on noncanonical PI3Kγ signalling.

Luo Qingyu Q Raulston Evangeline G EG Prado Miguel A MA Wu Xiaowei X Gritsman Kira K Whalen Karley S KS Yan Kezhi K Booth Christopher A G CAG Xu Ran R van Galen Peter P Doench John G JG Shimony Shai S Long Henry W HW Neuberg Donna S DS Paulo Joao A JA Lane Andrew A AA

Nature 20240508 8015

Phosphoinositide-3-kinase-γ (PI3Kγ) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers<sup>1-4</sup>. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukaemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid and dendritic lineages. This depe ...[more]

PMID: 38720074

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