Targeting leucine-rich repeat kinase 2 overcomes resistance to oncolytic herpes simplex virus-based therapies in glioblastoma - PubMed
3 hours ago
- #Glioblastoma
- #Oncolytic Virus
- #LRRK2 Inhibitor
- Glioblastoma (GBM) is an incurable brain tumor with high heterogeneity.
- Oncolytic viruses (OVs) are an approved therapy but limited by poor cellular permissiveness to infection.
- A brain-penetrant leucine-rich repeat kinase 2 (LRRK2) inhibitor was identified as the strongest enhancer of oncolytic herpes simplex virus (oHSV) in GBM.
- LRRK2 inhibition potentiates oHSV infection and oncolysis across diverse GBM cell lines and improves therapeutic outcomes in models.
- LRRK2 interacts with and promotes STAT1 phosphorylation at Y701, driving interferon-independent antiviral responses.
- LRRK2 inhibition attenuates host defenses, enhancing tumor-selective viral replication.
- Elevated LRRK2 levels in GBM correlate with reduced oHSV sensitivity, suggesting LRRK2 as a predictive biomarker.
- Combining LRRK2 inhibitors with oHSV is a promising therapeutic strategy for aggressive GBM.