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Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma

BACKGROUND: Neuroblastoma is a paediatric cancer that is characterised by poor prognosis for chemoresistant disease, highlighting the need for better treatment options. Here, we asked whether BH3-mimetics inhibiting BCL2 proteins may eliminate chemoresistant neuroblastoma cells. METHODS: We utilised...

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Autores principales: Jacob, Maureen, Wiedemann, Sara, Brücher, Daniela, Pieper, Nadja M., Birkhold, Moni, Särchen, Vinzenz, Jeroch, Jan, Demes, Melanie C., Gretser, Steffen, Braun, Yannick, Gradhand, Elise, Rothweiler, Florian, Michaelis, Martin, Cinatl, Jindrich, Vogler, Meike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10646009/
https://www.ncbi.nlm.nih.gov/pubmed/37723317
http://dx.doi.org/10.1038/s41416-023-02430-8
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author Jacob, Maureen
Wiedemann, Sara
Brücher, Daniela
Pieper, Nadja M.
Birkhold, Moni
Särchen, Vinzenz
Jeroch, Jan
Demes, Melanie C.
Gretser, Steffen
Braun, Yannick
Gradhand, Elise
Rothweiler, Florian
Michaelis, Martin
Cinatl, Jindrich
Vogler, Meike
author_facet Jacob, Maureen
Wiedemann, Sara
Brücher, Daniela
Pieper, Nadja M.
Birkhold, Moni
Särchen, Vinzenz
Jeroch, Jan
Demes, Melanie C.
Gretser, Steffen
Braun, Yannick
Gradhand, Elise
Rothweiler, Florian
Michaelis, Martin
Cinatl, Jindrich
Vogler, Meike
author_sort Jacob, Maureen
collection PubMed
description BACKGROUND: Neuroblastoma is a paediatric cancer that is characterised by poor prognosis for chemoresistant disease, highlighting the need for better treatment options. Here, we asked whether BH3-mimetics inhibiting BCL2 proteins may eliminate chemoresistant neuroblastoma cells. METHODS: We utilised cisplatin-adapted neuroblastoma cell lines as well as patient tissues before and after relapse to study alterations of BCL2 proteins upon chemoresistance. RESULTS: In a direct comparison of cisplatin-resistant cells we identified a prominent loss of sensitivity to BCL2/BCL-X(L) inhibitors that is associated with an increase in MCL1 dependency and high expression of MCL1 in patient tumour tissues. Screening of FDA-approved anti-cancer drugs in chemoresistant cells identified therapeutics that may be beneficial in combination with the clinically tested BH3-mimetic ABT263, but no synergistic drug interactions with the selective MCL1 inhibitor S63845. Further exploration of potential treatment options for chemoresistant neuroblastoma identified immunotherapy based on NK cells as highly promising, since NK cells are able to efficiently kill both parental and chemoresistant cells. CONCLUSIONS: These data highlight that the application of BH3-mimetics may differ between first line treatment and relapsed disease. Combination of NK cell-based immunotherapy with BH3-mimetics may further increase killing of chemoresistant neuroblastoma, outlining a new treatment strategy for relapsed neuroblastoma.
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spelling pubmed-106460092023-09-19 Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma Jacob, Maureen Wiedemann, Sara Brücher, Daniela Pieper, Nadja M. Birkhold, Moni Särchen, Vinzenz Jeroch, Jan Demes, Melanie C. Gretser, Steffen Braun, Yannick Gradhand, Elise Rothweiler, Florian Michaelis, Martin Cinatl, Jindrich Vogler, Meike Br J Cancer Article BACKGROUND: Neuroblastoma is a paediatric cancer that is characterised by poor prognosis for chemoresistant disease, highlighting the need for better treatment options. Here, we asked whether BH3-mimetics inhibiting BCL2 proteins may eliminate chemoresistant neuroblastoma cells. METHODS: We utilised cisplatin-adapted neuroblastoma cell lines as well as patient tissues before and after relapse to study alterations of BCL2 proteins upon chemoresistance. RESULTS: In a direct comparison of cisplatin-resistant cells we identified a prominent loss of sensitivity to BCL2/BCL-X(L) inhibitors that is associated with an increase in MCL1 dependency and high expression of MCL1 in patient tumour tissues. Screening of FDA-approved anti-cancer drugs in chemoresistant cells identified therapeutics that may be beneficial in combination with the clinically tested BH3-mimetic ABT263, but no synergistic drug interactions with the selective MCL1 inhibitor S63845. Further exploration of potential treatment options for chemoresistant neuroblastoma identified immunotherapy based on NK cells as highly promising, since NK cells are able to efficiently kill both parental and chemoresistant cells. CONCLUSIONS: These data highlight that the application of BH3-mimetics may differ between first line treatment and relapsed disease. Combination of NK cell-based immunotherapy with BH3-mimetics may further increase killing of chemoresistant neuroblastoma, outlining a new treatment strategy for relapsed neuroblastoma. Nature Publishing Group UK 2023-09-19 2023-11-09 /pmc/articles/PMC10646009/ /pubmed/37723317 http://dx.doi.org/10.1038/s41416-023-02430-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Jacob, Maureen
Wiedemann, Sara
Brücher, Daniela
Pieper, Nadja M.
Birkhold, Moni
Särchen, Vinzenz
Jeroch, Jan
Demes, Melanie C.
Gretser, Steffen
Braun, Yannick
Gradhand, Elise
Rothweiler, Florian
Michaelis, Martin
Cinatl, Jindrich
Vogler, Meike
Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma
title Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma
title_full Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma
title_fullStr Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma
title_full_unstemmed Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma
title_short Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma
title_sort increased mcl1 dependency leads to new applications of bh3-mimetics in drug-resistant neuroblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10646009/
https://www.ncbi.nlm.nih.gov/pubmed/37723317
http://dx.doi.org/10.1038/s41416-023-02430-8
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