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Proteasome inhibition as a potential therapeutic target in thymic cancer

Multimodal radio-chemotherapy is the mainstay of treatment for unresectable thymoma (TH) and thymic carcinoma (TC), but there is an urgent need for other therapeutic strategies in these rare tumors. The epithelial cells of the normal thymus express the three major proteasome classes: constitutive, i...

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Main Authors: Okada, Satoru (Author) , Benter, Louisa (Author) , Schrell, Leon (Author) , Müller, Denise (Author) , Selcen, Selen (Author) , Bohnenberger, Hanibal (Author) , Schneider, Carolin (Author) , Schneider, Günter (Author) , Lohrberg, Melanie (Author) , Koch, Raphael (Author) , Overbeck, Tobias R. (Author) , von Hammerstein-Equord, Alexander (Author) , Welter, Stefan (Author) , Hinterthaner, Marc (Author) , Cordes, Lucia (Author) , Shirneshan, Katayoon (Author) , Netzer, Christoph (Author) , Inoue, Masayoshi (Author) , Marx, Alexander (Author) , Ströbel, Philipp (Author) , Küffer, Stefan (Author)
Format: Article (Journal)
Language:English
Published: 04 December 2025
In: Cell death & disease
Year: 2025, Volume: 16, Pages: 1-11
ISSN:2041-4889
DOI:10.1038/s41419-025-08240-5
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41419-025-08240-5
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41419-025-08240-5
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Author Notes:Satoru Okada, Louisa Benter, Leon Schrell, Denise Müller, Selen Selcen, Hanibal Bohnenberger, Carolin Schneider, Günter Schneider, Melanie Lohrberg, Raphael Koch, Tobias R. Overbeck, Alexander von Hammerstein-Equord, Stefan Welter, Marc Hinterthaner, Lucia Cordes, Katayoon Shirneshan, Christoph Netzer, Masayoshi Inoue, Alexander Marx, Philipp Ströbel and Stefan Küffer
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Summary:Multimodal radio-chemotherapy is the mainstay of treatment for unresectable thymoma (TH) and thymic carcinoma (TC), but there is an urgent need for other therapeutic strategies in these rare tumors. The epithelial cells of the normal thymus express the three major proteasome classes: constitutive, immunoproteasome, and thymoproteasome, making thymic epithelial tumors potential candidates for treatment with proteasome inhibitors. In a drug screen of 120 cytotoxic agents, the two thymic carcinoma cell lines 1889c and MP57 showed exquisite sensitivity to the proteasome inhibitor carfilzomib (PR-171). Immunohistochemistry, gene expression, and in vitro functional studies were used in a comprehensive sample collection to investigate the correlation between immunoproteasome subunit expression and response to carfilzomib. 50% of TC and a substantial proportion of TH strongly expressed immunoproteasome subunits and showed functional activity of β1i (PSMB9), β2i (PSMB10), and β5i (PSMB8). INF-γ treatment induced immunoproteasome expression and increased cell sensitivity to carfilzomib, while siRNA knockdown reduced carfilzomib response in vitro. Carfilzomib synergized with BCL2 family protein inhibitors (navitoclax or AZD5991), suggesting that drug combinations could be used to reduce the dose of each drug to minimize toxicity. Notably, thymic carcinomas differed from squamous cell carcinomas in other organs by higher levels of β5i (PSMB8) and constitutive proteasome β5 (PSMB5). We hypothesize that TC (and probably many TH) are uniquely suited for treatment with proteasome inhibitors alone or in combination with selective BH3 mimetics.
Item Description:Online veröffentlicht: 04. Dezember 2025
Gesehen am 11.02.2026
Physical Description:Online Resource
ISSN:2041-4889
DOI:10.1038/s41419-025-08240-5

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