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Phosphoinositide-3-kinase-γ (PI3Kγ) has been suggested as a target for tumor-associated macrophage repolarization and promotion of anti-tumor immune responses in solid cancers. However, the intrinsic role of PI3Kγ in cancer cells is not well understood.
On May 8, 2024, Qingyu Luo et al. from Harvard Medical School published a research paper entitled "Targetable leukaemia dependency on noncanonical PI3Kγ signalling" online in Nature, which defined high-risk subpopulations (including myeloid, lymphoid and dendritic lineages) by integrating unbiased genome-wide CRISPR interference screening and functional analysis of acute leukemia Selective dependence on PI3Kγ complexes. This dependence is characterized by innate inflammatory signaling and activation of phosphorylated inosine kinase regulatory subunit 5 (PIK3R5), which encodes the regulatory subunit of PI3Kγ5 and stabilizes the active enzyme complex.
p21 (RAC1)-activated kinase 1 (PAK1) is a non-canonical substrate of PI3Kγ, mediating this cellular intrinsic dependence, and inhibition of PAK1 dephosphorylation by PI3Kγ has been found to impair mitochondrial oxidative phosphorylation. The selective PI3Kγ inhibitor eganelisib is effective in the treatment of PIK3R5-activated leukemia. In addition, the combination of eganelisib and cytarabine prolonged survival than either drug alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells treated with cytarabine had elevated G-protein-coupled purinergic receptor activity and PAK1 phosphorylation. In conclusion, this study reveals a targetable dependence on PI3Kγ-PAK1 signaling in patients with acute leukemia and can be used for short-term evaluation.
Despite recent advances in targeted therapies targeting certain genetic subsets of acute leukemia, many disease subtypes lack mechanotargeted therapy, and most patients have a poor long-term prognosis. Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are the two most common types of acute leukemia. Maternal plasmacytoid dendritic cell tumour (BPDCN) is an aggressive hematologic malignancy that arises from a plasmacytoid dendritic cell lineage and shares the same clinical and pathological features as AML and ALL. Treatment that targets CD123 expressed on the cell surface has been approved for BPDCN and has been tested in other acute leukemias, including AML, but it does not directly target cell-intrinsic carcinogenic pathways. The investigators hypothesize that the overlapping features between BPDCN and other acute leukemias may indicate that functionally related subsets of hematologic malignancies share therapeutic vulnerability. The mammalian PI3K family contains multiple isoforms of several classes. Class I PI3Ks are classified into class IA and IB and produce inositol 3-phosphate lipids, which activate signal transduction pathways, and class II and III PI3Ks are regulators of endocytic membrane trafficking. Class IA PI3Ks include three catalytic subunits α, β, and δ (encoded by PIK3CA, PIK3CB, and PIK3CD, respectively), and regulatory subunits p85α, p55α, p50α, p85β, and p55γ (encoded by PIK3R1, PIK3R2, and PIK3R3)5. Class IB PI3K has only one catalytic subunit, p110γ (encoded by PIK3CG) and two regulatory subunits, p101 and p84 (encoded by PIK3R5 and PIK3R6, respectively), and is activated by G protein-coupled receptors (GPCRs) via heterotrimers and small G proteins. Several cancers have activated class IA PI3K, and many pathway inhibitors have been approved or are in development. In contrast, the class IB PI3K component (i.e., enzymatic p110γ and regulatory subunits) has received less attention, and the therapeutic focus has been limited to reprogramming macrophages with PI3Kγ inhibitors for immunotherapy in solid tumors. The role of PI3Kγ as a cellular intrinsic cancer driver is unclear.
白血病依赖于非规范PI3Kγ信号（Credit: Nature）
The study found that leukemia subsets characterized by congenital inflammatory signal-activated PIK3R5 were highly sensitive to PI3Kγ inhibition. The increased PIK3R5 and PIK3CG appear to form a self-stabilizing complex capable of translating modest transcriptional elevation of PIK3R5 into substantial activation of PI3Kγ. Surprisingly, the intrinsic dependence of leukemia on PI3Kγ is not related to the traditional PI3K substrate AKT4, but rather on phosphorylation of PAK1 kinase. PI3Kγ inhibition inactivates RAC1 and reduces its interaction with PAK1, thereby demonstrating the presence of the PI3Kγ-RAC1-PAK1 signaling pathway in this leukemia subset. Therefore, the study found that PAK1(S144) phosphorylation was significantly associated with the response to eganelisib in primary AML samples. Several ATP-competitive and ATP-noncompetitive PAK allosteric inhibitors are available, which may help address these issues and provide another therapeutic node targeting this pathway. As predicted, this combination plays a synergistic role in the model with elevated PIK3R5. The combination is also effective in leukemia with low baseline PIK3R5 and may be related to G-protein-coupled purinergic receptor signaling and PAK1 phosphorylation in glycosidine-persistent leukemia cells. In conclusion, this study reveals a targetable dependence on PI3Kγ-PAK1 signaling in patients with acute leukemia and can be used for short-term evaluation.
Original link https://www.nature.com/articles/s41586-024-07410-3
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文章来源|“ iNature”
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