RANKL acts an unfavorable prognostic biomarker and potential target in advanced KRAS‐mutated lung adenocarcinoma

OBJECTIVE: Advanced lung cancers carrying Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation remain a group that lacks effective treatments. Receptor activator of nuclear factorκB ligand (RANKL) has been demonstrated to drive malignant phenotypes in lung cancer; however, its role in KRAS‐mutant (mt) lung adenocarcinoma (LUAD) is not yet fully elucidated. MATERIALS AND METHODS: The data used to explore expression and prognosis were obtained from The Cancer Genome Atlas, Genotype‐Tissue Expression databases, and from our hospital. The proliferation, invasion, and migration capacities of KRAS‐mt LUAD cells were evaluated. The prediction model was established via Lasso regression method. RESULTS: RANKL is strongly expressed in advanced KRAS‐mt LUAD, and significantly distinct association exists between high RANKL expression and poor survival. The enriched expression of RANKL in advanced KRAS‐mt LUAD was confirmed by specimens from our hospital. Further, although not statistically significant, our clinical cohort (n = 57) revealed a longer median progression‐free survival in advanced KRAS‐mt LUAD patients treated with RANKL inhibitor than those without (300 vs. 133 days, p = 0.210), but not in KRAS‐wt ones (208 vs. 250 days, p = 0.334). Decrease of KRAS‐mt LUAD cells’ capacity for proliferation, invasion, and migration was observed when RANKL was knocked down. Enrichment analysis suggested distinct roles of RANKL between KRAS‐mt and KRAS‐wt LUAD, with adhesion‐related pathways and molecules significantly downregulated in the KRAS‐mt RANKL‐high tumors. Finally, a model for predicting overall survival of KRAS‐wt LUAD was established according to four related key genes (BCAM, ICAM5, ITGA3, and LAMA3), which had good performance in prediction concordance. CONCLUSIONS: RANKL acts as an unfavorable prognostic biomarker for patients with advanced KRAS‐mt LUAD. Inhibition of RANKL may be a feasible strategy for this subset of patients.