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

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 profil...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	MCL-1 BCL-xL BH3 mimetics Thymoma Thymic carcinoma Medicine R
Acceso en línea:	https://doaj.org/article/2194d474c86a458e93ca84edcaf6e9e8
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spelling	oai:doaj.org-article:2194d474c86a458e93ca84edcaf6e9e82021-11-21T12:16:01ZFunctional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas10.1186/s12916-021-02158-31741-7015https://doaj.org/article/2194d474c86a458e93ca84edcaf6e9e82021-11-01T00:00:00Zhttps://doi.org/10.1186/s12916-021-02158-3https://doaj.org/toc/1741-7015Abstract 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.Denise MüllerPaolo MazzeoRaphael KochMark-Sebastian BösherzStefan WelterAlexander von Hammerstein-EquordMarc HinterthanerLucia CordesDjeda BelharazemAlexander MarxPhilipp StröbelStefan KüfferBMCarticleMCL-1BCL-xLBH3 mimeticsThymomaThymic carcinomaMedicineRENBMC Medicine, Vol 19, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	MCL-1 BCL-xL BH3 mimetics Thymoma Thymic carcinoma Medicine R
spellingShingle	MCL-1 BCL-xL BH3 mimetics Thymoma Thymic carcinoma Medicine R 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 Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas
description	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.
format	article
author	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
author_facet	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
author_sort	Denise Müller
title	Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas
title_short	Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas
title_full	Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas
title_fullStr	Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas
title_full_unstemmed	Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas
title_sort	functional apoptosis profiling identifies mcl-1 and bcl-xl as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas
publisher	BMC
publishDate	2021
url	https://doaj.org/article/2194d474c86a458e93ca84edcaf6e9e8
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Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas

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