Introduction: NSCLC is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF‐&kgr;B (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy. Methods: Receptor activator of NF‐&kgr;B gene (RANK) and receptor activator of NF‐&kgr;B ligand gene (RANKL) expression in human lung adenocarcinoma was interrogated from publicly available gene expression data sets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK‐Fc to block RANKL, with primary tumor growth measured longitudinally using microcomputed tomography. A combination of RANKL blockade with cisplatin was tested to mirror an ongoing clinical trial. Results: In human lung adenocarcinoma data sets, RANKL expression was associated with decreased survival and KRAS mutation, with the highest levels in tumors with co‐occurring KRAS and liver kinase B1 gene (LKB1) mutations. In KrasLSL‐G12D/WT, KrasLSL‐G12D/WT; Lkb1Flox/Flox and KrasLSL‐G12D/WT; p53Flox/Flox mouse models of lung adenocarcinoma, we monitored an impaired progression of tumors upon RANKL blockade. Despite elevated expression of RANKL and RANK in immune cells, treatment response was not associated with major changes in the tumor immune microenvironment. Combined RANK‐Fc with cisplatin revealed increased efficacy compared with that of single agents in p53‐ but not in Lkb1‐deficient tumors. Conclusions: RANKL blocking agents impair the growth of primary lung tumors in several mouse models of lung adenocarcinoma and suggest that patients with KRAS‐mutant lung tumors will benefit from such treatments.

中文翻译：

---

RANKL 信号在肺腺癌基因工程小鼠模型中维持原发肿瘤生长

简介：NSCLC是癌症死亡的主要原因。最近的回顾性临床分析表明，阻断 NF-&kgr;B (RANK) 信号通路的受体激活剂可抑制 NSCLC 的生长，并可能代表一种新的治疗策略。方法：从公开可用的基因表达数据集中查询人肺腺癌中 NF-&kgr;B 基因受体激活剂 (RANK) 和 NF-&kgr;B 配体基因受体激活剂 (RANKL) 表达。几种基因工程小鼠模型被用于评估 RANK-Fc 阻断 RANKL 的治疗效果，并使用微计算机断层扫描纵向测量原发性肿瘤的生长。对 RANKL 阻断剂与顺铂的组合进行了测试，以反映正在进行的临床试验。结果：在人肺腺癌数据集中，RANKL 表达与存活率降低和 KRAS 突变相关，在同时发生 KRAS 和肝激酶 B1 基因（LKB1）突变的肿瘤中表达水平最高。在 KrasLSL-G12D/WT、KrasLSL-G12D/WT；Lkb1Flox/Flox 和 KrasLSL-G12D/WT；p53Flox/Flox 肺腺癌小鼠模型，我们监测了 RANKL 阻断后肿瘤的受损进展。尽管免疫细胞中 RANKL 和 RANK 的表达升高，但治疗反应与肿瘤免疫微环境的重大变化无关。与单药相比，RANK-Fc 与顺铂的组合在 p53 中显示出更高的疗效，但在 Lkb1 缺陷肿瘤中则没有。结论：