文章：

嗜色性肾细胞癌中BCL-xL的依赖性

BCL-xL dependency in chromophobe renal cell carcinoma 

原文发布日期：2025-08-16 

英文摘要：

Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of kidney cancer, with limited therapeutic options. Using BH3 profiling to screen ChRCC-derived cell lines, we discovered that BH3 peptides targeting BCL-xL promote apoptosis in ChRCC. Downregulation of BCL2L1 is sufficient to induce apoptosis in ChRCC-derived cells, consistent with our screening results. BCL2L1, encoding BCL-xL, is fourfold upregulated in ChRCC compared to normal kidney and has the second highest expression in The Cancer Genome Atlas. BCL2L1 downregulation enhances MCL-1 expression, suggesting a possible compensatory role for MCL-1. Based on these results, we evaluated two BH3 mimetics, A-1331852 (targeting BCL-xL) and S63845 (targeting MCL-1). Their combination resulted in 80% cell death. DT2216, a proteolysis-targeting chimera (PROTAC) that targets BCL-xL for degradation, induced cleaved PARP and caspase 3, indicators of apoptosis. ChRCC cells are known to be highly sensitive to ferroptosis. We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). BCL-xL and MCL-1 inhibition enhanced the susceptibility to ferroptosis, suggesting a link between apoptosis and ferroptosis in ChRCC. These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy. 

摘要翻译：

嫌色细胞肾细胞癌（ChRCC）是第三常见的肾癌亚型，治疗方案有限。通过使用BH3分析技术筛选ChRCC来源的细胞系，我们发现靶向BCL-xL的BH3肽能促进ChRCC细胞凋亡。BCL2L1基因的下调足以诱导ChRCC来源细胞凋亡，这与我们的筛选结果一致。编码BCL-xL的BCL2L1基因在ChRCC中的表达量是正常肾组织的四倍，在癌症基因组图谱中表达水平位居第二。BCL2L1下调会增强MCL-1表达，提示MCL-1可能具有代偿作用。基于这些结果，我们评估了两种BH3模拟物：靶向BCL-xL的A-1331852和靶向MCL-1的S63845。联合使用这两种药物可导致80%的细胞死亡。而靶向降解BCL-xL的蛋白水解靶向嵌合体（PROTAC）DT2216能诱导PARP和caspase 3的裂解，这些都是细胞凋亡的标志物。已知ChRCC细胞对铁死亡高度敏感。我们将A-1331852和S63845分别与铁死亡诱导剂IKE或RSL3联用。抑制BCL-xL和MCL-1可增强对铁死亡的敏感性，提示ChRCC中细胞凋亡与铁死亡存在关联。这些数据表明BCL-xL通过抑制凋亡来维持ChRCC细胞存活。目前正处于临床试验阶段的BCL-xL特异性PROTAC药物DT2216可能为ChRCC治疗提供新机遇。

原文链接：

BCL-xL dependency in chromophobe renal cell carcinoma