Metastatic lung adenocarcinoma (LuAC) presents a significant clinical challenge due to the short latency and the lack of efficient treatment options. Therefore, identification of molecular vulnerabilities in metastatic LuAC holds great importance in the development of therapeutic drugs against this disease. In this study, we performed a genome-wide siRNA screening using poorly and highly brain-metastatic LuAC cell lines. Using this approach, we discovered that compared to poorly metastatic LuAC (LuAC-Par) cells, brain-metastatic LuAC (LuAC-BrM) cells exhibited a significantly higher vulnerability to (an inhibitor of caspase-8)depletion-induced apoptosis. Furthermore, studies demonstrated that knockdown specifically inhibited growth of LuAC-BrM, but not the LuAC-Par, tumors, suggesting the addiction of LuAC-BrM to the function of c-FLIP for their survival.

中文翻译：

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系统鉴定脑转移性肺腺癌中的合成致死相互作用

由于潜伏期短且缺乏有效的治疗方案，转移性肺腺癌（LuAC）提出了重大的临床挑战。因此，识别转移性 LuAC 的分子脆弱性对于开发针对该疾病的治疗药物具有重要意义。在这项研究中，我们使用低度和高度脑转移的 LuAC 细胞系进行了全基因组 siRNA 筛选。使用这种方法，我们发现与转移性较差的 LuAC (LuAC-Par) 细胞相比，脑转移性 LuAC (LuAC-BrM) 细胞对（caspase-8 抑制剂）耗竭诱导的细胞凋亡表现出明显更高的脆弱性。此外，研究表明敲除特异性抑制 LuAC-BrM 肿瘤的生长，但不抑制 LuAC-Par 肿瘤的生长，这表明 LuAC-BrM 依赖于 c-FLIP 的功能来维持其生存。