Targeting LPAR1 as a potential therapeutic strategy for glioblastoma

Glioblastoma (GBM) is the most aggressive primary brain tumor, with a poor prognosis and a 5-year survival rate of 10%, despite multimodal treatment combining surgery, radiotherapy, and chemotherapy. Due to its high invasiveness, complete surgical resection is challenging, making postoperative radiotherapy and chemotherapy indispensable. Temozolomide (TMZ), a DNA alkylating agent, remains the only FDA-approved therapeutic agent for GBM, novel therapeutic agents for GBM are warranted. In this study, to identify potential therapeutic targets in GBM, we conducted an siRNA-based screening of G protein-coupled receptors (GPCRs) and identified lysophosphatidic acid receptor 1 (LPAR1) as a key molecule whose knockdown significantly reduced the GBM cell viability. LPA, a bioactive lipid mediator, signals through six receptors (LPAR1-6), with LPAR1 particularly implicated in cytoskeletal remodeling, migration, proliferation, and differentiation. Analysis of TCGA data revealed that LPAR1 is highly expressed in brain tumors compared to other cancer types. In vitro , LPAR1 knockdown significantly suppressed cell proliferation and induced PARP cleavage, a hallmark of apoptosis, in several GBM cell lines expressing LPAR1. LPA treatment enhanced proliferation of LPAR1-positive GBM cell lines in a concentration-dependent manner and this effect was cancelled by both genetic and pharmacological inhibition of LPAR1. These results indicate that the LPA-LPAR1 axis plays a critical role in promoting GBM cell proliferation and survival. Further analysis using phospho-Kinase arrays and pathway-specific inhibitors revealed that the PI3K/Akt signaling pathway downstream of LPAR1 is involved in these pro-survival effects. In an orthotopic GBM xenograft model, oral administration of the LPAR1 antagonist BMS-986020 significantly suppressed tumor growth in brain. Additionally, combinatorial treatment with BMS-986020 and TMZ lowered the IC ₅₀ value of TMZ in vitro , suggesting a potential synergistic cytotoxic effect. We have previously reported the potential of LPAR1 antagonists as therapeutic agents for osteosarcoma (Takagi S et al. Oncogene 2021); our current findings suggest that LPAR1 antagonists would be promising therapeutic option for GBM treatment.