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

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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