Using BRAFV600E as a marker of autophagy dependence in pediatric brain tumors

Abstract

Autophagy inhibition is a potential therapeutic strategy in central nervous system (CNS) tumors. The BRAFV600E mutation is known to affect autophagy. Our studies indicate CNS tumor cells with BRAFV600E mutant cells (but not wild type) display high rates of induced autophagy, are sensitive to autophagy inhibition, and display synergy when chloroquine is combined with the RAF kinase inhibitor vemurafenib or standard chemotherapeutics. Our studies also indicate chloroquine can improve vemurafenib sensitivity in intrinsically resistant cells and in a patient with induced-vemurafenib resistance. These findings suggest CNS tumors with BRAFV600E are autophagy-dependent and that identification of BRAFV600E may be a marker to identify pediatric patients with the best potential response to autophagy inhibition.