Abstract 1006P
Background
Receptor activator of nuclear factorκB ligand (RANKL) has been shown to drive proliferation and migration in lung cancer; however, its role in KRAS-mutant (KRAS-MT) lung adenocarcinoma (LUAD) is not fully elucidated.
Methods
Pan-cancer was analyzed by TIMER2, and expression and survival differentials of RANKL for both pan-cancer and LUAD were discovered using RNA-sequencing and clinical data from the TCGA database. Signaling pathways linked to RANKL expression within KRAS-MT LUAD were discovered using single-sample Gene Set Enrichment Analysis (ssGSEA). The proliferation, migration, and invasion capacities of LUAD cells (both in KRAS-WT [H322] and MT [H427] ones) after knockdown of RANKL were evaluated by fluorescence cell counting, CCK-8 proliferation assay, wound-healing assay, and transwell migration assay. A retrospective cohort (n = 131) of advanced LUAD patients carrying bone metastases from the Chinese National Cancer Center treated with RANKL inhibitor denosumab (DN group) or phosphates (PS group) was used for clinical validation.
Results
RANKL is strongly expressed in most malignancies including LUAD, and distinct associations exist between high RANKL expression and poor survival in LUAD patients, especially for KRAS-MT ones. Tumor proliferation signature, angiogenesis, epithelial-mesenchymal transition markers, and cell cycle-related signaling pathways were all enriched in the presence of elevated RANKL expression in KRAS-MT LUAD, according to ssGSEA analysis. LUAD cells' capacity for proliferation, migration, and invasion was decreased when RANKL was knocked down, which was more pronounced in KRAS-MT ones. Our single-center clinical cohort revealed a lower risk of disease progression in DN group than that in PS group (hazard ratio [HR] = 0.653, 95% confidence interval [CI]: 0.379-1.124, p = 0.156) for the overall population, and this trend was more pronounced in the KRAS-MT group (HR = 0.554, 95% CI: 0.256-1.202, p = 0.169), especially for KRAS-G12C subgroup (HR = 0.395, 95% CI: 0.105-1.485, p = 0.209), though significant differences were not confirmed.
Conclusions
RANKL further promotes the malignant phenotypes of KRAS-MT LUAD relative to KRAS-WT LUAD, and inhibition of RANKL may be a feasible strategy for KRAS-MT LUAD.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.