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

Autor: Müller D; Institute of Pathology, University Medical Center Göttingen, University of Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany., Mazzeo P; Department of Haematology and Medical Oncology, University Medical Centre Göttingen, Göttingen, Germany., Koch R; Department of Haematology and Medical Oncology, University Medical Centre Göttingen, Göttingen, Germany., Bösherz MS; Institute of Pathology, University Medical Center Göttingen, University of Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany., Welter S; Thoracic Surgery Department, Lung Clinic Hemer, Hemer, Germany., von Hammerstein-Equord A; Department of Heart, Thoracic and Vascular Surgery, University Medical Center Göttingen, Göttingen, Germany., Hinterthaner M; Department of Thoracic and Cardiovascular Surgery, University Medical Center, Göttingen, Germany., Cordes L; Thoracic Surgery Department, Lung Clinic Hemer, Hemer, Germany., Belharazem D; Institute of Pathology, University Medical Centre Mannheim and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Marx A; Institute of Pathology, University Medical Centre Mannheim and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Ströbel P; Institute of Pathology, University Medical Center Göttingen, University of Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. philipp.stroebel@med.uni-goettingen.de., Küffer S; Institute of Pathology, University Medical Center Göttingen, University of Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Jazyk: angličtina
Zdroj: BMC medicine [BMC Med] 2021 Nov 16; Vol. 19 (1), pp. 300. Date of Electronic Publication: 2021 Nov 16.
DOI: 10.1186/s12916-021-02158-3
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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