Treatment of Novel Patient-Derived Xenograft and Cell Line Models with PI3K/AKT/mTOR Inhibitors Revealed Treatment Response Heterogeneity in NF2-Associated Schwannoma

Treatment of multiple intracranial schwannomas in patient with neurofibromatosis type 2 (NF2) is extremely unsatisfactory and innovative therapeutic approaches are urgently needed. The lack of clinically relevant NF2 models has severely hampered drug discovery in this rare disease. Here, we report for the first time the establishment and characterization of patient-derived xenograft (PDX) and cell line models of NF2-associated schwannoma, which retain the gene mutations and transcriptome profile, and recapitulate the morphological and histopathological features with the patient tumors, retain patient NF2 mutations, and maintain gene expression profiles resembling the patient tumor profiles with the preservation of multiple key signaling pathways commonly dysregulated in human schwannoma. Using expression profiling, we found that the PI3K/AKT/mTOR networks are elevated in NF2-associated vestibular schwannomas, as well as in PDX models. Overall design: 9 NF2-associated schwannoma samples were analysed: three primary tumour samples,three patient-derived xenografts in grown in nude mice, and three established immortalized cell lines