Issues

Mulcahy Levy and colleagues report that autophagy is increased in BRAF^V600E-positive pediatric central nervous system (CNS) tumors, suggesting that BRAF-mutant CNS tumors may be dependent on autophagy. Indeed, inhibition of autophagy was cytotoxic to BRAF^V600E-positive CNS tumor cells, and the autophagy inhibitor chloroquine showed synergistic activity with the BRAF inhibitor vemurafenib in BRAF-mutant CNS tumor cells. The addition of chloroquine to vemurafenib overcame vemurafenib resistance in primary BRAF-mutant pleomorphic xanthoastrocytoma cells, and combined chloroquine and vemurafenib rapidly improved symptoms and led to durable disease stabilization in a patient with vemurafenib-refractory BRAF^V600E-positive brainstem ganglioglioma. These findings provide a rationale for combining autophagy inhibitors with BRAF-targeted therapy in patients with BRAF-mutant CNS tumors. For details, please see the article by Mulcahy Levy and colleagues on page 773.