Autophagy inhibition improves chemosensitivity in BRAF(V600E) brain tumors.
Autophagy inhibition is a potential therapeutic strategy in cancer, but it is unknown which tumors will benefit. The BRAF(V600E) mutation has been identified as important in pediatric central nervous system (CNS) tumors and is known to affect autophagy in other tumor types. We evaluated CNS tumor cells with BRAF(V600E) and found that mutant (but not wild-type) cells 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 that 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 the addition of chloroquine can improve clinical outcomes. These findings suggest that CNS tumors with BRAF(V600E) are autophagy-dependent and should be targeted with autophagy inhibition in combination with other therapeutic strategies.


CONCLUSIONS
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 in which deliberate autophagy inhibition halted tumor growth and overcame acquired BRAF-inhibition resistance.
Authors' Affiliations: Departments of Pediatrics, Jean.Mulcahy-Levy@childrenscolorado.org.
Jean M Mulcahy
JM
Levy
Authors' Affiliations: Departments of Pediatrics.
Joshua C
JC
Thompson
Authors' Affiliations: Departments of Pediatrics.
Andrea M
AM
Griesinger
Authors' Affiliations: Departments of Pediatrics.
Vladimir
V
Amani
Authors' Affiliations: Departments of Pediatrics.
Andrew M
AM
Donson
Neurosurgery.
Diane K
DK
Birks
Pharmacology, and.
Michael J
MJ
Morgan
Radiology, University of Colorado Denver, Aurora, Colorado.
David M
DM
Mirsky
Neurosurgery.
Michael H
MH
Handler
Authors' Affiliations: Departments of Pediatrics.
Nicholas K
NK
Foreman
Pharmacology, and.
Andrew
A
Thorburn
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology; D002648:Child; D002738:Chloroquine / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib
D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D002738:Chloroquine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf