{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE343nnn/GSE343216/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE343216"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"The mesenchymal state of NF1-associated malignant peripheral nerve sheath tumor is vulnerable to synergistic p53-pathway activation by combined MEK and MDM2 inhibition","description":"Malignant 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.","dates":{"publication":"2026/09/01"},"accession":"GSE343216","cross_references":{"GSM":["GSM9947893","GSM9947850","GSM9947894","GSM9947891","GSM9947892","GSM9947890","GSM9947857","GSM9947858","GSM9947899","GSM9947855","GSM9947856","GSM9947853","GSM9947897","GSM9947854","GSM9947898","GSM9947851","GSM9947895","GSM9947896","GSM9947852","GSM9947859","GSM9947860","GSM9947861","GSM9947868","GSM9947901","GSM9947902","GSM9947869","GSM9947866","GSM9947867","GSM9947900","GSM9947864","GSM9947865","GSM9947862","GSM9947863","GSM9947909","GSM9947907","GSM9947908","GSM9947905","GSM9947906","GSM9947903","GSM9947904","GSM9947871","GSM9947872","GSM9947870","GSM9947879","GSM9947912","GSM9947913","GSM9947910","GSM9947877","GSM9947911","GSM9947878","GSM9947875","GSM9947876","GSM9947873","GSM9947874","GSM9947882","GSM9947883","GSM9947880","GSM9947881","GSM9947888","GSM9947889","GSM9947886","GSM9947887","GSM9947884","GSM9947885"],"GPL":["24247"],"GSE":["343216"],"taxon":["Mus musculus"]}}