已传文件：photo/1773121782.png
Article Information
Glioblastoma (GBM) is the most malignant type of brain tumor, characterized by high heterogeneity and treatment resistance. Traditional therapies have limited efficacy, with a median survival period of less than 15 months. Oncolytic viruses (OVs) are a newly approved treatment for GBM, but their clinical application is limited by the low infection tolerance of tumor cells, and they are only effective for some patients.
Recently, a team from Xiamen University published a significant study in "Nature Communications", revealing for the first time that targeting leucine-rich repeat kinase 2 (LRRK2) can effectively overcome the treatment resistance of GBM to oncolytic herpes simplex virus (oHSV), providing a new strategy for combined treatment of GBM. The related research results have laid a solid foundation for clinical translation.
Key analysis
Core finding: LRRK2 inhibitors are potent sensitizers for oHSV
The research team first screened 1593 bioactive compounds to find small molecule compounds that could enhance the activity of oHSV in GBM cells. Eventually, LRRK2 inhibitors (such as LRRK2-IN-1) were found to be the most effective sensitizers, with a combined index (CI) of 45.94%, much higher than other candidate compounds.
Further verification showed that LRRK2-IN-1 could enhance the killing effect of oHSV on various GBM cell lines (including patient-derived cell lines GBM-1) in a dose-dependent manner, showing strong synergistic inhibitory effects in 6 GBM cells; it could also significantly enhance the cytotoxicity of oHSV on glioblastoma stem cells (GSCs), and other LRRK2 inhibitors (PFE-360, MLi-2, etc.) could achieve similar sensitizing effects.
Key data: Pretreatment with LRRK2-IN-1 significantly reduced the half-inhibitory concentration (EC₅₀) of oHSV in different GBM cells, with EC₅₀ of U-251 MG and U-118 MG cells decreasing by 10.42 times and 20.17 times, respectively; knocking down LRRK2 could increase the sensitivity of GBM cells to oHSV infection, with viral replication increasing by 2-4 times, while overexpression of LRRK2 would significantly reduce the infection sensitivity.
Mechanism of action: LRRK2 mediates antiviral innate immunity through regulating the STAT1 pathway
The research used RNA-seq, co-immunoprecipitation, kinase experiments, and other methods to clarify the core mechanism of LRRK2-mediated oHSV resistance:
Direct interaction and phosphorylation:
LRRK2 can directly bind to STAT1 (the binding domain is the RocCOR domain of LRRK2 and the DB/SH2 domain of STAT1), and directly phosphorylate the Y701 site of STAT1, activating the STAT1 signaling pathway;
Driving antiviral response:
The activated STAT1 would upregulate the expression of interferon-stimulated genes (ISGs, such as IFIT2, IRF9, OAS2, etc.) and trigger an interferon-independent antiviral innate immune response, inhibiting the replication and oncolytic effect of oHSV;
Inhibitor effect:
LRRK2 inhibitors can significantly inhibit the phosphorylation of STAT1 Y701, downregulate the expression of ISGs, weaken the antiviral defense of tumor cells, thereby promoting the selective replication and spread of oHSV in tumors, and enhancing the apoptosis of tumor cells induced by oHSV (caspase-3/7, caspase-9 activity significantly upregulated). Furthermore, the study also discovered a new signaling axis of TBK1-LRRK2-STAT1-ISGs. TBK1 can regulate the phosphorylation of LRRK2, thereby affecting the activation of downstream STAT1, providing new targets for the regulation of this pathway.
In vivo verification: The combined therapy significantly inhibits tumor growth and prolongs survival
The study verified the efficacy of the LRRK2 inhibitor combined with oHSV therapy in patient-derived xenograft (PDX) models and immune-healthy orthotopic GBM models (GL261):
PDX model:
: The combined treatment significantly enhanced the replication of oHSV within the tumor, significantly inhibiting the growth of GBM-1 tumors starting from the 15th day, with the tumor burden being significantly lower than that of the oHSV monotherapy group on the 30th day (P = 0.0003), and increasing tumor cell apoptosis and reducing the expression of IRF9; Original link: https://doi.org/10.1038/s41467-026-70132-9
