Title: Autophagy Inhibition Improves Chemosensitivity in BRAF Brain Tumors

Autophagy inhibition is a potential therapeutic strategy in cancer, but it is unknown which tumors will benefit. The BRAF mutation has been identified as important in pediatric CNS tumors and is known to affect autophagy in other tumor types. We evaluated CNS tumor cells with BRAF and found that mutant cells (but not wild type) display high rates of induced autophagy, are sensitive to pharmacologic and genetic autophagy inhibition, and display synergy when the clinically used autophagy inhibitor chloroquine was combined with the Raf inhibitor vemurafenib or standard chemotherapeutics. Importantly we also demonstrate chloroquine can improve vemurafenib sensitivity in a resistant ex vivo primary culture and provide the first demonstration in a patient harboring the V600E mutation treated with vemurafenib that addition of chloroquine can improve clinical outcomes. These findings suggest CNS tumors with BRAF are autophagy-dependent and should be targeted with autophagy inhibition in combination with other therapeutic strategies. Statement of Significance: Autophagy inhibition may improve cancer therapy but it is unclear which tumors will benefit. We found that BRAF mutations cause brain tumor cells to depend on autophagy and display selective chemosensitization with autophagy inhibition. We present a pediatric case where deliberate autophagy inhibition halted tumor growth and overcome acquired BRAF-inhibition resistance. Research. on July 5, 2017. © 2014 American Association for Cancer cancerdiscovery.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 13, 2014; DOI: 10.1158/2159-8290.CD-14-0049