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NF1-Mutated Tumors Exhibit Increased Sensitivity to Autophagy Inhibition Alone and in Combination with MEK Inhibition

Baird-Daniel, Eliza and Zahedi, Shadi and Morin, Andrew and Desmarais, Michelle and Williams, Kyle and Williams, Rory and Vibhakar, Rajeev and Foreman, Nicholas and Mulcahy-Levy, Jean (2021) NF1-Mutated Tumors Exhibit Increased Sensitivity to Autophagy Inhibition Alone and in Combination with MEK Inhibition. Neuro Oncology, 23 (S1). i44. ISSN 1522-8517. doi:10.1093/neuonc/noab090.179. https://resolver.caltech.edu/CaltechAUTHORS:20210819-230526338

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Abstract

Background: Autophagy inhibition is a potential treatment for central nervous system (CNS) tumors. Autophagy, a heavily regulated process by which cellular waste is transferred to lysosomes for degradation and processing, is an integral part of tumor cell survival under stressful conditions including nutrient deprivation and chemotherapy. While the efficacy of autophagy inhibition has been demonstrated in CNS tumors with BRAF^(V600e) mutations, it has yet to be explored in other CNS tumor types with MAPK pathway dysregulation including NF1-mutated tumors. Many tumors associated with the NF1 phenotype can be difficult to treat surgically thus development of further pharmacologic interventions is necessary. Methods: A CRISPR/Cas9 mediated NF1 KO was derived from human immortalized Schwann cells and utilized as a tumor model. Autophagy inhibition was achieved pharmacologically by chloroquine (CQ) and genetically via shRNAi of ATG5 and ATG7. Trametinib was used for MEK inhibition. Cell growth and viability were determined by Incucyte, Cell Titer-Glo luminescent assay, and colony-formation assays. Protein expression was measured by western blot. Results: We demonstrate increased autophagic activity in NF1 KO cell as compared to control lines both at baseline and in response to cellular stress. Furthermore, we describe that NF1 KO cells exhibit increased sensitivity to CQ alone, CQ in combination with trametinib, and shRNAi-mediated autophagy inhibition in combination with trametinib. Conclusion: Here, we describe increased autophagic dependence of NF1 mutated tumors and demonstrate increased tumor sensitivity to autophagy inhibition both alone and in combination with MEK inhibition. These findings indicate that autophagy inhibition via CQ may be an effective adjunctive treatment for NF1 mutated tumors and suggests that diverse CNS tumor types with MAPK pathway dysregulation are susceptible to autophagy inhibition. Clinical investigation of combined MEK and autophagy inhibition has the potential to improve outcomes for NF1 patients with CNS tumors.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1093/neuonc/noab090.179DOIArticle
Additional Information:© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Published: 01 June 2021.
Subject Keywords:phenotype; chloroquine; western blotting; mutation; cell growth; central nervous system; chemotherapy regimen; central nervous system neoplasms; autophagy; cell survival; inhibition (psychology); lysosomes; mitogen-activated protein kinases; schwann cells; neoplasms; pharmacology; stress; nutrients; braf gene; tumor model; catabolism; trametinib; crispr
Issue or Number:S1
DOI:10.1093/neuonc/noab090.179
Record Number:CaltechAUTHORS:20210819-230526338
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210819-230526338
Official Citation:Eliza Baird-Daniel, Shadi Zahedi, Andrew Morin, Michelle Desmarais, Kyle Williams, Rory Williams, Rajeev Vibhakar, Nicholas Foreman, Jean Mulcahy-Levy, NF1-Mutated Tumors Exhibit Increased Sensitivity to Autophagy Inhibition Alone and in Combination with MEK Inhibition, Neuro-Oncology, Volume 23, Issue Supplement_1, June 2021, Page i44, https://doi.org/10.1093/neuonc/noab090.179
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110313
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:20 Aug 2021 16:53
Last Modified:20 Aug 2021 16:53

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