Targetable leukaemia dependency on noncanonical PI3Kγ signalling

Qingyu Luo, Evangeline G. Raulston, Miguel A. Prado, Xiaowei Wu, Kira Gritsman, Karley S. Whalen, Kezhi Yan, Christopher A. G. Booth, Ran Xu, Peter Galen, John G. Doench, Shai Shimony, Henry W. Long, Donna S. Neuberg, Joao A. Paulo and Andrew A. Lane ()
Additional contact information
Qingyu Luo: Harvard Medical School
Evangeline G. Raulston: Harvard Medical School
Miguel A. Prado: Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)
Xiaowei Wu: Dana-Farber Cancer Institute
Kira Gritsman: Albert Einstein College of Medicine
Karley S. Whalen: Harvard Medical School
Kezhi Yan: Harvard Medical School
Christopher A. G. Booth: Harvard Medical School
Ran Xu: Harvard Medical School
Peter Galen: Brigham and Women’s Hospital
John G. Doench: Broad Institute of MIT and Harvard
Shai Shimony: Harvard Medical School
Henry W. Long: Harvard Medical School
Donna S. Neuberg: Dana-Farber Cancer Institute
Joao A. Paulo: Harvard Medical School
Andrew A. Lane: Harvard Medical School

Nature, 2024, vol. 630, issue 8015, 198-205

Abstract: Abstract Phosphoinositide-3-kinase-γ (PI3Kγ) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers1–4. 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 dependency is characterized by innate inflammatory signalling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3Kγ5 and stabilizes the active enzymatic complex. We identify p21 (RAC1)-activated kinase 1 (PAK1) as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency and find that dephosphorylation of PAK1 by PI3Kγ inhibition impairs mitochondrial oxidative phosphorylation. Treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukaemias with activated PIK3R5. In addition, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukaemia xenografts with low baseline PIK3R5 expression, as residual leukaemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Together, our study reveals a targetable dependency on PI3Kγ–PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia.

Date: 2024
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DOI: 10.1038/s41586-024-07410-3

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