Institute of Pathology, University Medical Center Göttingen, University of Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Department of Haematology and Medical Oncology, University Medical Centre Göttingen, Göttingen, Germany.
BMC Med. 2021 Nov 16;19(1):300. doi: 10.1186/s12916-021-02158-3.
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.
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.
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.
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.
多组学研究表明，大多数胸腺瘤（TH）和胸腺癌（TC）中存在高频率且缺乏常见驱动突变，这阻碍了新治疗方法的发展。然而，凋亡失调已被提出作为 TH 和 TC 的共同标志。BH3 谱分析可用于研究活癌细胞发生凋亡的准备情况及其对生存 BCL-2 家族蛋白的依赖性。
我们筛选了 62 例 TH 和 TC 患者样本，检测 BCL-2 家族蛋白的表达，并利用 TC 细胞系 1889c 和天然 TH 进行动态 BH3 谱分析和 BH3 模拟物治疗。
MCL-1 和 BCL-xL 的免疫组化过表达是 TH 和 TC 的强烈预后标志物，BH3 谱分析表明 TH 对 MCL-1 和 BCL-xL 有很强的依赖性。MCL-1 的单抑制导致 BIM 与 BCL-xL 的结合增加，作为一种逃逸机制，可被联合抑制两种因子克服。事实上，MCL-1 和 BCL-xL 的联合抑制以半胱天冬酶依赖的方式诱导未经处理和 MCL-1 耐药的 1889c 细胞凋亡。
TH 和 TC 对生存因子 MCL-1 和 BCL-xL 具有极高的依赖性，使其成为 BH3 模拟物联合抑制的理想候选药物。由于 TH 对 BCL-2 家族蛋白的依赖性存在异质性，因此在开始时进行 BH3 谱分析可以选择患者，并针对个体情况制定最佳治疗方案，以尽可能减少毒性。
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