Targetable leukaemia dependency on noncanonical PI3K? signalling

Fecha de publicación: 06/06/2024 Fecha Ahead of Print: 01/05/2024

Autores con afiliación ISPA

Miguel Ángel Prado Rodríguez

Autor

Otros autores

Luo, QY
Raulston, EG
Wu, XW
Gritsman, K
Whalen, KS
Yan, KZ
Booth, CAG
Xu, R
van Galen, P
Doench, JG
Shimony, S
Long, HW
Neuberg, DS
Paulo, JA
Lane, AA

Grupos y Plataformas

Proteómica y Proteostasis

Investigador/a Responsable

Miguel Ángel Prado Rodríguez

Abstract

Phosphoinositide-3-kinase-gamma (PI3K gamma) 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 PI3K gamma are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukaemias, we define a selective dependency on the PI3K gamma 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 PI3K gamma 5 and stabilizes the active enzymatic complex. We identify p21 (RAC1)-activated kinase 1 (PAK1) as a noncanonical substrate of PI3K gamma that mediates this cell-intrinsic dependency and find that dephosphorylation of PAK1 by PI3K gamma inhibition impairs mitochondrial oxidative phosphorylation. Treatment with the selective PI3K gamma 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 PI3K gamma-PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia. Using a multimodal approach across acute leukaemias, a targetable PI3K gamma dependency in leukaemias is explored.