CNSC-28. IDENTIFICATION OF EAG2-KVß2 POTASSIUM CHANNEL COMPLEX IN NEURON-GBM COMMUNICATIONS REVEALS GBM VULNERABILITY TO DESIGNER INTERFERENCE PEPTIDE

Abstract Glioblastomas (GBMs) are the most aggressive brain tumors. GBM cells form extensive tumoral networks to communicate with each other and surrounding neurons. Neuronal activity promotes cell proliferation by secreting protumorigenic factors triggering neuronal-activity-dependent Ca2+ transients, which persisted transmitted via tumor promote overall growth therapy resistance. While how these processes regulated is largely unknown. Here we show transients a voltage-gated potassium channel complex comprised of EAG2 Kvβ2. selectively overexpress Kvβ2 isoform 4 facilitate tumor-specific Kvβ2-EAG2 interaction, regulates neuron-GBM contact-dependent localization EAG2. Rationally designed interfering peptide K90-114TAT blocks EAG2-Kvβ2 leading reduced proliferation, increased apoptosis, prolonged survival patient-derived xenograft mouse models no evidence toxicity normal tissue. Single-cell RNA sequencing revealed subgroup highly sensitive treatment. These exhibit neuronal signatures associated TMZ resistance worse prognosis. In accordance notion, found neurons cells, complex. Treating TMZ-resistant mice yielded significant burden reduction survival. Together, our findings as key regulator neuron promoted progression an anti-GBM efficacy low general toxicity, may have clinical impact.