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Open Access 01-12-2021 | Thymoma | Research article

Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas

Authors: Denise Müller, Paolo Mazzeo, Raphael Koch, Mark-Sebastian Bösherz, Stefan Welter, Alexander von Hammerstein-Equord, Marc Hinterthaner, Lucia Cordes, Djeda Belharazem, Alexander Marx, Philipp Ströbel, Stefan Küffer

Published in: BMC Medicine | Issue 1/2021

Abstract

Background

Multi-omics studies have shown a high and lack of common driver mutations in most thymomas (TH) and thymic carcinomas (TC) that hamper the development of novel treatment approaches. However, deregulation of apoptosis has been proposed as a common hallmark of TH and TC. BH3 profiling can be utilized to study the readiness of living cancer cells to undergo apoptosis and their dependency on pro-survival BCL-2 family proteins.

Methods

We screened a cohort of 62 TH and TC patient samples for expression of BCL-2 family proteins and used the TC cell line 1889c and native TH for dynamic BH3 profiling and treatment with BH3 mimetics.

Results

Immunohistochemical overexpression of MCL-1 and BCL-xL was a strong prognostic marker of TH and TC, and BH3 profiling indicated a strong dependency on MCL-1 and BCL-xL in TH. Single inhibition of MCL-1 resulted in increased binding of BIM to BCL-xL as an escape mechanism that the combined inhibition of both factors could overcome. Indeed, the inhibition of MCL-1 and BCL-xL in combination induced apoptosis in a caspase-dependent manner in untreated and MCL-1-resistant 1889c cells.

Conclusion

TH and TC are exquisitely dependent on the pro-survival factors MCL-1 and BCL-xL, making them ideal candidates for co-inhibition by BH3 mimetics. Since TH show a heterogeneous dependency on BCL-2 family proteins, upfront BH3 profiling could select patients and tailor the optimal therapy with the least possible toxicity.

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Title: Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas
Authors: Denise Müller
Paolo Mazzeo
Raphael Koch
Mark-Sebastian Bösherz
Stefan Welter
Alexander von Hammerstein-Equord
Marc Hinterthaner
Lucia Cordes
Djeda Belharazem
Alexander Marx
Philipp Ströbel
Stefan Küffer
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Thymoma
Thymoma
Published in: BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-02158-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas

Abstract

Background

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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