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

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

doi:10.1186/s12916-021-02158-3

Abstract

BackgroundMulti-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.MethodsWe 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.ResultsImmunohistochemical 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.ConclusionTH 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.

Highlights

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
Expression of MCL-1 and BCL-xL has prognostic relevance in TH and TC To investigate the prognostic impact of the BCL-2 family proteins, we performed IHC stainings of TP53, BCL-2, MCL-1, BCL-xL, and the pro-apoptotic factor NOXA in 62 TH and TC with known clinical history (Table 1 and Fig. 1A)
Our findings indicate that any clinical trial using B-cell lymphoma homology 3 (BH3) mimetics in the thymus (TET) should ideally address both MCL-1 and BCL-xL

Summary

Introduction

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. Thymomas (TH) and thymic carcinomas (TC) are rare epithelial tumors of the thymus (TET). The World Health Organization (WHO) classifies TH into type A, AB, B1, B2, and B3 according to the morphology of the neoplastic epithelial cells and the proportion of immature lymphocytes [1]. TH show organotypic features, such as epithelial cells with cortical and medullary differentiation [2] and the capacity to promote the maturation of thymocytes. Chemotherapy is the most common treatment for relapsed TET. Tyrosine kinase inhibitors such as sunitinib may be an option for relapsing TC [5, 6]. The overall response rates are typically high [7, 8], most tumors eventually become refractory to these treatments

Methods

Results

Discussion

Conclusion