SNX-2112 inhibits the ERBB3 ^high tumor population in Plexiform Neurofibromas

Plexiform neurofibroma (PN) is a monogenic disorder affecting the Schwann cell lineage in approximately half of Neurofibromatosis type 1 patients. It often manifests in early childhood and carries a risk of malignant transformation at puberty. While MEK inhibitors have recently been approved for pediatric and adult patients, their long-term clinical benefits remain uncertain due to adverse effects, particularly in pediatrics. The ERBB3 ^high stem-like tumor cell subpopulation reflects the intrinsic PN heterogeneity and can serve as alternative druggable targets. Characterization using molecular signatures also reveals the heterogeneity within the PN cell lines, and the PN drug screen analysis proposes that SNX-2112, an HSP90 inhibitor, can inhibit PN cell viability by targeting ERBB3-associated signaling. Our in vitro results demonstrated a significant viability reduction in ERBB3 ^high PN cells compared to the controls. Treatment with SNX-2112 led to a decrease in total ERBB3, p-ERBB3 (Tyr1289), and the downstream total AKT and p-AKT (Ser473) levels. Furthermore, the significant in vivo inhibitory efficacy of SNX-2112 was revealed using a transplantation model from mouse PN with DhhCreNF1 ^f/f ; Luc configuration. These findings support the efficacy of SNX-2112 as a potential alternative therapeutic strategy, highlighting its possible application in PN patients.