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Combining brigatinib with mTOR inhibition to effectively treat NF2-SWN-associated and sporadic NF2-deficient meningiomas

ABSTRACT: We previously generated an orthotopic, NF2-deficient meningioma model using the luciferase-expressing Ben-Men-1 cell line established from a sporadic tumor and identified the multi-kinase inhibitor brigatinib and the mTOR kinase inhibitor INK128 to potently impede tumor growth. Here, we describe generation of the telomerase-immortalized AG-NF2-Men cell line from a grade-1 meningioma of an NF2-related schwannomatosis (NF2-SWN) patient. We showed that like Ben-Men-1 cells, AG-NF2-Men cells were NF2-null, expressed several NF2-regulated receptor tyrosine kinases, and responded to their cognate ligands. We also found that brigatinib and INK128 alone inhibited AG-NF2-Men cell proliferation at IC50 values similar to those in Ben-Men-1 cells. Combining brigatinib with INK128 exhibited growth-inhibitory synergy. Mechanistically, the combination not only completely abrogated p-AKT(S473) and its downstream signaling compared to either drug alone but also prevented INK128-mediated re-phosphorylation of AKT on T308. Also, the combination more-effectively blocked ligand-mediated phosphorylation of EGFR, ErbB3, and IGF-1R and elicited major changes in the expression of genes including the upstream regulators of several signaling networks important for meningioma growth. Further, we generated luciferase-expressing AG-NF2-Men cells that readily grew as intracranial xenografts. Importantly, combining brigatinib with INK128 enhanced tumor regression in both the orthotopic AG-NF2-Men and Ben-Men-1 xenograft models. As the first NF2-SWN-related meningioma cell line, AG-NF2-Men is a unique reagent for investigating meningioma biology and therapeutics. A clinical trial to evaluate the combination of brigatinib with an mTOR inhibitor in NF2-deficient meningiomas is warranted.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307286 | GEO | 2025/09/05

REPOSITORIES: GEO

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Project description:Introduction: Meningiomas are the most common primary central nervous system tumors, constituting 39.7% of intracranial tumors. Although generally benign, some exhibit aggressive be-havior and risk of recurrence, necessitating adjuvant therapy and repeat surgical in-terventions. Molecular studies have identified tumor-driving mutations, leading to tar-geted therapies and clinical trials. However, translating preclinical findings into clinical success is often hindered by limitations in current meningioma tumor models. This study aims to develop and validate a standardized protocol for establishing patient-derived meningioma organoids (MEN-O) that faithfully replicate human disease. Methods: We obtained meningioma samples from neurosurgical resections and MEN-O were developed using an optimized culture protocol. Histological and immunohistochemical analyses were used to assess the resemblance of MEN-O to original tumor tissues. RNA sequencing compared transcriptional signatures between MEN-O and corresponding patient-resected tissues. Results: MEN-O were successfully established from patient-resected samples and maintained in culture for up to four weeks, showing stable growth and structural integrity. Histopathological analysis revealed that MEN-O preserved key architectural features, including cellular organization, nuclear mor-phology, and proliferation rates. Immunohistochemical staining for meningioma-specific markers, such as progesterone receptor, confirmed similar expression patterns to parental tumors. Transcriptomic profiling demonstrated that MEN-O retained the transcriptional signatures of original tissues, including genes associated with meningioma pathology (NF2, CDKN2A, TP53). Differential expression and deconvolution analyses showed that MEN-O contained diverse cell populations, including tumor and stromal cells, while preserving the immune microenvironment, as validated by histopathological and tran-scriptomic profiling. Conclusion: We established a robust, reproducible protocol for generating MEN-O, which faithfully replicates the histopathological, molecular, and cellular characteristics of original tumors. MEN-O provide a valuable model for studying meningioma biology and evaluating therapeutic strategies.

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Combining brigatinib with mTOR inhibition to effectively treat NF2-SWN-associated and sporadic NF2-deficient meningiomas

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