The mesenchymal state of NF1-associated malignant peripheral nerve sheath tumor is vulnerable to synergistic p53-pathway activation by combined MEK and MDM2 inhibition

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE343216 | GEO | 2026/09/01

REPOSITORIES: GEO