美国丹娜-法伯癌症研究所Andrew A. Lane团队近期取得重要工作进展，他们研究提出靶向白血病对非经典PI3Kγ信号传导的依赖性观点。相关研究成果2024年5月8日在线发表于《自然》杂志上。

据介绍，磷脂酰肌醇-3-激酶-γ（PI3Kγ）被认为是实体癌中肿瘤相关巨噬细胞再极化和促进抗肿瘤免疫反应的靶点。然而，癌症细胞PI3Kγ的内在作用尚不清楚。

通过将无偏好的全基因组CRISPR干扰筛查与急性白血病的功能分析相结合，研究人员定义了包括骨髓、淋巴和树突状谱系在内的高危亚群对PI3Kγ复合物的选择性依赖。这种依赖性的特征是固有的炎症信号传导和磷酸肌醇3-激酶调节亚基5（PIK3R5）的激活，PIK3R5编码PI3Kγ的调节亚基并稳定活性酶复合物。研究人员确定p21（RAC1）-活化激酶1（PAK1）是PI3Kγ的非经典底物，介导这种细胞内在依赖性，并发现PI3Kγ抑制对PAK1的去磷酸化损害线粒体氧化磷酸化。选择性PI3Kγ抑制剂eganelisib治疗活化PIK3R5的白血病是有效的。

此外，eganelisib和阿糖胞苷联合使用比单独使用任何一种药物都能延长生存期，即使在基线PIK3R5表达较低的患者来源的白血病异种移植物中也是如此，因为阿糖胞苷治疗后残留的白血病细胞具有升高的G蛋白偶联嘌呤能受体活性和PAK1磷酸化。

总之，这一研究揭示了对PI3Kγ-PAK1信号传导的靶向依赖性，可用于急性白血病患者的近期评估。

附：英文原文

Title: Targetable leukaemia dependency on noncanonical PI3Kγ signalling

Author: Luo, Qingyu, Raulston, Evangeline G., Prado, Miguel A., Wu, Xiaowei, Gritsman, Kira, Whalen, Karley S., Yan, Kezhi, Booth, Christopher A. G., Xu, Ran, van Galen, Peter, Doench, John G., Shimony, Shai, Long, Henry W., Neuberg, Donna S., Paulo, Joao A., Lane, Andrew A.

Issue&Volume: 2024-05-08

Abstract: Phosphoinositide-3-kinase-γ (PI3Kγ) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers1,2,3,4. 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.

DOI: 10.1038/s41586-024-07410-3

Source: https://www.nature.com/articles/s41586-024-07410-3