Targeting RANKL-independent osteoclastogenesis overcomes denosumab resistance in models of ER+ breast cancer bone metastasis
Qun Lin, Jinpeng Luo, Zhuxi Duan, Jieer Luo, Wei Zhang, Yuan Xia, Yinduo Zeng, Xiaolin Fang, Jiahui Liang, Jiayi Chen, Qianchong Lin, Yilin Quan, Ruiyu Hu, Hongcai Liu, Qiang Liu, Jun Li, Chang Gong
Qun Lin, Jinpeng Luo, Zhuxi Duan, Jieer Luo, Wei Zhang, Yuan Xia, Yinduo Zeng, Xiaolin Fang, Jiahui Liang, Jiayi Chen, Qianchong Lin, Yilin Quan, Ruiyu Hu, Hongcai Liu, Qiang Liu, Jun Li, Chang Gong
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Research Article Cell biology Oncology

Targeting RANKL-independent osteoclastogenesis overcomes denosumab resistance in models of ER+ breast cancer bone metastasis

Abstract

Bone metastasis remains a major cause of morbidity in estrogen receptor–positive breast cancer, with RANKL inhibitor resistance emerging as a critical clinical challenge. Nearly 40% of patients develop progressive skeletal lesions despite denosumab therapy, highlighting an urgent need to identify resistance mechanisms and alternative therapeutic strategies. We identified a RANKL-independent osteoclast activation pathway mediated by the CRKL/circCCDC50/NFATc1 axis. Mechanistically, CRKL promoted EIF4A3-dependent circCCDC50 biogenesis, which was packaged into large oncosomes and transferred to osteoclast precursors. Nuclear circCCDC50 recruited CARM1 to epigenetically activate NFATc1 transcription, establishing a self-reinforcing loop that sustained osteolysis despite RANKL blockade. Pharmacological inhibition of CARM1 (TP-064) effectively suppressed osteoclastogenesis and bone metastasis in denosumab-resistant models. These findings revealed a targetable resistance mechanism and provided a clinically actionable strategy to overcome microenvironment-driven metastasis through dual targeting of tumor and bone niches.

Authors

Qun Lin, Jinpeng Luo, Zhuxi Duan, Jieer Luo, Wei Zhang, Yuan Xia, Yinduo Zeng, Xiaolin Fang, Jiahui Liang, Jiayi Chen, Qianchong Lin, Yilin Quan, Ruiyu Hu, Hongcai Liu, Qiang Liu, Jun Li, Chang Gong

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Figure 10

CARM1 is recruited by circCCDC50 to the NFATc1 promoter, where it mediates H3R17me2a enrichment.

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CARM1 is recruited by circCCDC50 to the NFATc1 promoter, where it mediat...
(A) CARM1 occupancy at the NFATc1 promoter was elevated in BMMs treated with LOs derived from primary tumor cells by ChIP-qPCR. NFATc1 promoter (+) indicates the CARM1 enrichment at the NFATc1 promoter region; NFATc1 promoter (–) indicates the CARM1 enrichment at a negative control region. anti-CARM1 (+) indicates ChIP with an anti-CARM1 antibody; anti-CARM1 (–) indicates ChIP with a control IgG antibody. (B) H3R17me2a enrichment at the NFATc1 promoter region was elevated in BMMs treated with LOs derived from primary tumor cells by ChIP-qPCR. NFATc1 promoter (+) indicates the H3R17me2a enrichment at the NFATc1 promoter region; NFATc1 promoter (–) indicates the enrichment at a negative control region. (C) Representative IF images of circCCDC50 (red) and CARM1 (green) in cells with or without CARM1 knockdown. (D) Upper: Schematic of CARM1 protein domains. Lower: Immunoblot (IB) validation of truncated CARM1 constructs confirming the intermediate domain (aa 200–400) as essential for circCCDC50 binding. Each error bar represents the mean ± SD of 3 independent experiments. Significant differences were determined by 1-way ANOVA with Tukey’s multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001.