Targeting RANKL-Independent Osteoclastogenesis Overcomes Denosumab Resistance in ER+ Breast Cancer Bone Metastasis [RNA-seq]

Bone metastasis remains a major cause of morbidity in ER+ 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 promotes EIF4A3-dependent circCCDC50 biogenesis, which is packaged into large oncosomes and transferred to osteoclast precursors. Nuclear circCCDC50 recruits CARM1 to epigenetically activate NFATc1 transcription, establishing a self-reinforcing loop that sustains osteolysis despite RANKL blockade. Pharmacological inhibition of CARM1 (TP-064) effectively suppresses osteoclastogenesis and bone metastasis in denosumab-resistant models. These findings reveal a targetable resistance mechanism and provide a clinically actionable strategy to overcome microenvironment-driven metastasis through dual targeting of tumor and bone niches.