DDDR-06. NEUROFIBROMATOSIS TUMOR SUPPRESSORS COOPERATIVELY DRIVE TUMOR DE-DIFFERENTIATION AND MEK INHIBITOR RESISTANCE IN PERIPHERAL NERVOUS SYSTEM TUMORS

Abstract Schwann cell derived tumors comprising schwannomas, neurofibromas, and malignant peripheral nerve sheath (MPNSTs) are the most common cancers of nervous system often arise in patients with neurofibromatosis type-1 (NF-1) or type-2 (NF-2). NF-1 is caused by loss NF1, a negative regulator Ras signaling, NF-2 NF2, pleiotropic tumor suppressor numerous functions including inhibition PAK signaling. However, whether functional interactions exist between NF1 NF2 suppressors remain unclear. More broadly, there currently no effective molecular therapies for beyond MEK inhibitor selumetinib to treat neurofibromas NF-1. Here, we integrate DNA methylation profiling, whole exome sequencing, bulk single-cell RNA biochemistry, pharmacology across human samples, lines, mouse xenografts identify cellular de-differentiation as driver transformation resistance. Single nuclear RNA-sequencing (n = 3) MPNSTs revealed total 13 types increased proliferating, de-differentiated populations MPNST samples. persistence treated samples compared vehicle control, suggesting underlies treatment A genome-wide CRISPRi screen mediators response deficient neurofibroma cells drives Consistently, suppression activation PAK, serine threonine kinase. Translationally, small molecule combination formed an therapy xenografts. In sum, elucidate paradigm driving resistance tumors, uncovering link that sheds light on novel therapeutic vulnerability.