Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors
Open accessAbstract
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 BRAFV600E inhibitor 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 with BRAFV600E brain tumors.
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Proficient autophagic responses most often mediate cytoprotective rather than cytotoxic effects in adaptation to stress.
“Proficient autophagic responses (which are under tight transcriptional and post-translational regulation) [509 799–805] most often operate at the hub of adaptation to stress, hence mediating cytoprotective (rather than cytotoxic) effects [806–811].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [808]
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- Authors
- Mulcahy Levy, J. M., Zahedi, S., Griesinger, A. M., Morin, A., Davies, K. D., Aisner, D. L., Kleinschmidt-DeMasters, B., Fitzwalter, B. E., Goodall, M. L., Thorburn, J., Amani, V., Donson, A. M., Birks, D. K., Mirsky, D. M., Hankinson, T. C., Handler, M. H., Green, A. L., Vibhakar, R., Foreman, N. K., & Thorburn, A.
- Affiliations
- Department of Pediatrics, University of Colorado Denver, Aurora, United States
- Morgan Adams Foundation (US)
- University of Colorado Denver (US)
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-01-17
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5241115
- OpenAlex
- W2576152476
- Cited by
- 175
- References
- 39
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 17 · 2023: 16 · 2022: 22 · 2021: 25 · 2020: 20 · 2019: 29 · 2018: 16 · 2017: 10
- FWCI
- 16.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (K08CA193982, P30CA046934, R01CA150925, RO1CA190170)
- U.S. Department of Defense (W81XWH-14-0414)
- St. Baldrick's Foundation (elope, Inc. St. Baldrick's Foundation Scholar Award)
- Alex's Lemonade Stand Foundation for Childhood Cancer (Young Investigator Award)
- Morgan Adams Foundation (Morgan Adams Research Science Award)
- Olivia Caldwell Foundation (Low Grade Glioma Grant)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- autophagy inhibition, BRAF V600E mutation, vemurafenib resistance, kinase inhibitor resistance, pediatric brain tumors, chloroquine, combination therapy, autophagy
- MeSH terms
- Vemurafenib, Antineoplastic Agents, Autophagy, Brain Neoplasms, Cell Survival, Chloroquine, Drug Synergism, Humans, Indoles, Sulfonamides, Treatment Outcome, Drug Resistance, Neoplasm, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Cell Proliferation
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