逃避细胞凋亡可促进肿瘤存活，并有助于头颈鳞状细胞癌 (HNSCC) 对癌症治疗产生耐药性。我们最近的工作表明，HNSCC 高度表达促生存抗凋亡蛋白 Bcl-xL 和 Mcl-1。然而，HNSCC逃避细胞凋亡的机制仍不清楚。我们使用 BH3 分析（一种测量引入 BH3 肽后线粒体去极化的功能测定）来评估一组永生化和患者来源的 HNSCC 系中的凋亡能力和对 BCL-2 家族抗凋亡蛋白的依赖性。我们评估了对 BH3 模拟物的反应，包括 ABT-263 (navitoclax)（一种 Bcl-2/Bcl-xL/Bcl-w 抑制剂）和 S63845（一种 Mcl-1 抑制剂），无论是单药还是联合用药。我们证明，大多数 HNSCC 细胞中的凋亡信号似乎是完整的，并且它们共同依赖于 Bcl-xL 和 Mcl-1 来生存。我们发现该组合在 HHNSCC 的 2D 培养和 3D 类器官模型中具有高度协同作用。鉴于我们发现 Bcl-xL 和 Mcl-1 的共同依赖性很常见，并且这些分子的共同抑制对于 HNSCC 细胞的生长抑制具有协同作用，这些结果阐明了 BCL-xL 和 MCL-1 抑制在 HNSCC 细胞中的治疗潜力。 HNSCC.版权所有 © 2024 Elsevier Ltd. 保留所有权利。

Evasion of apoptosis promotes tumor survival and contributes to resistance to cancer therapeutics in head and neck squamous cell carcinoma (HNSCC). Our recent work has demonstrated that HNSCC's highly express pro-survival anti-apoptotic proteins Bcl-xL and Mcl-1. Nevertheless, the mechanism of HNSCC to evade apoptosis is still not well understood. We used BH3 profiling, a functional assay which measures mitochondrial depolarization in response to the introduction of BH3 peptides, to evaluate apoptosis competency and dependency upon BCL-2 family anti-apoptotic proteins in a panel of immortalized and patient-derived HNSCC lines. We assessed response to BH3 mimetics including ABT-263 (navitoclax), an inhibitor of Bcl-2/Bcl-xL/Bcl-w, and S63845, an inhibitor of Mcl-1, both as single agents and in combination. We demonstrate that apoptosis signaling appears to be intact in the majority of HNSCC cells, and they are co-dependent upon Bcl-xL and Mcl-1 for survival. We found the combination to be highly synergistic in 2D culture and in 3D organoid models of HHNSCC. Given our findings that co-dependency on Bcl-xL and Mcl-1 is common, and co-inhibition of these molecules is synergistic for growth suppression in HNSCC cells, these results elucidate the therapeutic potential of BCL-xL and MCL-1 inhibition in HNSCC.Copyright © 2024 Elsevier Ltd. All rights reserved.