GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE343nnn/GSE343216/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE343216GEOGSEfalseThe mesenchymal state of NF1-associated malignant peripheral nerve sheath tumor is vulnerable to synergistic p53-pathway activation by combined MEK and MDM2 inhibitionMalignant peripheral nerve sheath tumor (MPNST) is unique as a mesenchymal neoplasm/sarcoma arising from benign plexiform neurofibroma (PNF), a neuroepithelial-derived Schwann cell (SC) tumor associated with neurofibromatosis type 1 (NF1). Using genetically engineered mouse models, we show that Nf1 loss efficiently induced RAS-MEK-ERK/MAPK-driven PNFs from developmentally abnormal nonmyelinating SCs, but no SC/epithelial-to-mesenchymal transition (EMT) or MPNST. Additional loss of Cdkn2a or p53 was required for Nf1-deficient PNFs to progress into MPNSTs. Using a high-throughput drug-repurposing screen and p53-off/on switchable system, we uncovered that MEK inhibition (MEKi) reduced Mdm2/MDM2 expression and activated p53-mediated apoptosis, which was curbed by the p53-MDM2 negative feedback loop, but overcome by MDM2 inhibitors (MDM2i). Importantly, combined MEKi/MDM2i treatment eliminated MEKi- and MDM2i-induced resistant MPNSTs by synergistically activating p53-mediated MEKi-induced apoptosis and MDM2i-driven EMT reversal with SC differentiation. Thus, the mesenchymal state of MPNST is vulnerable to p53-pathway activation, providing a therapeutic strategy for this incurable cancer.2026/09/01GSE343216GSM9947893GSM9947850GSM9947894GSM9947891GSM9947892GSM9947890GSM9947857GSM9947858GSM9947899GSM9947855GSM9947856GSM9947853GSM9947897GSM9947854GSM9947898GSM9947851GSM9947895GSM9947896GSM9947852GSM9947859GSM9947860GSM9947861GSM9947868GSM9947901GSM9947902GSM9947869GSM9947866GSM9947867GSM9947900GSM9947864GSM9947865GSM9947862GSM9947863GSM9947909GSM9947907GSM9947908GSM9947905GSM9947906GSM9947903GSM9947904GSM9947871GSM9947872GSM9947870GSM9947879GSM9947912GSM9947913GSM9947910GSM9947877GSM9947911GSM9947878GSM9947875GSM9947876GSM9947873GSM9947874GSM9947882GSM9947883GSM9947880GSM9947881GSM9947888GSM9947889GSM9947886GSM9947887GSM9947884GSM994788524247343216Mus musculus