Summary
Hypothesis Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-κB (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy.
Methods RANK and RANKL expression in human lung adenocarcinoma was interrogated from publicly available gene expression datasets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK-Fc to block RANKL, with primary tumor growth measured longitudinally using micro-computed tomography. A combination of RANKL blockade with cisplatin was tested to mirror an ongoing clinical trial.
Results In human lung adenocarcinoma datasets, RANKL expression was associated with decreased survival and KRAS mutation, with the highest levels in tumors with co-occurring KRAS and 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 to single agents.
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.
Footnotes
This work was supported by the Swiss Cancer Research Foundation (KFS-3458-08-2014), the Swiss National Science Foundation, and the National Center of Competence in Research (NCCR) in Molecular Oncology.
The authors declare no conflict of interest.