title: Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors.
abstract: Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors.BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600Einhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients withBRAFV600Ebrain tumors.
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, United States.|Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.
authors.forename: Jean M
authors.identifier: 0000-0002-3022-4246
authors.initials: JM
authors.lastname: Mulcahy Levy
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, United States.|Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.
authors.forename: Shadi
authors.initials: S
authors.lastname: Zahedi
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, United States.|Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Griesinger
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, United States.|Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morin
authors.affiliation: Department of Pathology, University of Colorado Denver, Aurora, United States.
authors.forename: Kurtis D
authors.initials: KD
authors.lastname: Davies
authors.affiliation: Department of Pathology, University of Colorado Denver, Aurora, United States.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Aisner
authors.affiliation: Department of Pathology, University of Colorado Denver, Aurora, United States.|Department of Neurosurgery, University of Colorado Denver, Aurora, United States.
authors.forename: B K
authors.initials: BK
authors.lastname: Kleinschmidt-DeMasters
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, United States.
authors.forename: Brent E
authors.initials: BE
authors.lastname: Fitzwalter
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, United States.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Goodall
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, United States.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Thorburn
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, United States.|Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Amani
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, United States.|Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Donson
authors.affiliation: Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.|Department of Neurosurgery, University of Colorado Denver, Aurora, United States.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Birks
authors.affiliation: Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.|Department of Radiology, University of Colorado Denver, Aurora, United States.
authors.forename: David M
authors.initials: DM
authors.lastname: Mirsky
authors.affiliation: Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.|Department of Neurosurgery, University of Colorado Denver, Aurora, United States.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Hankinson
authors.affiliation: Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.|Department of Neurosurgery, University of Colorado Denver, Aurora, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Handler
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, United States.|Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Green
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, United States.|Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, United States.|Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, United States.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D002738:Chloroquine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF V600E; autophagy; brain tumor; cancer biology; cell biology; chloroquine; human; pediatric