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Updated: May 17, 2026
Development of a Human Preclinical Model of Osteoclastogenesis from Peripheral Blood Monocytes Co-cultured with Breast Cancer Cell Lines
Published on: September 13, 2017
Targeting RANKL-independent osteoclastogenesis overcomes denosumab resistance in models of ER+ breast cancer bone
Qun Lin1,2, Jinpeng Luo1,2, Zhuxi Duan1,2
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
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.
Insights
A new pathway drives bone metastasis in breast cancer resistant to RANKL inhibitors. Targeting CARM1 with TP-064 suppressed osteoclast formation and bone lesions in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Bone metastasis is a significant complication of estrogen receptor-positive breast cancer.
- Resistance to denosumab (a RANKL inhibitor) is a major clinical problem, with ~40% of patients experiencing disease progression.
- There is a critical need to understand resistance mechanisms and develop alternative therapies.
Purpose of the Study:
- To identify novel mechanisms of osteoclast activation independent of RANKL signaling.
- To elucidate the role of the CRKL/circCCDC50/NFATc1 axis in denosumab-resistant bone metastasis.
- To evaluate the therapeutic potential of targeting this pathway in preclinical models.
Main Methods:
- Investigated a RANKL-independent osteoclast activation pathway.
- Utilized molecular biology techniques to study CRKL, circCCDC50, and NFATc1 interactions.
- Employed oncosome transfer assays and epigenetic analysis.
- Tested the efficacy of CARM1 inhibition (TP-064) in denosumab-resistant bone metastasis models.
Main Results:
- Identified a CRKL/circCCDC50/NFATc1 axis mediating RANKL-independent osteoclast activation.
- Demonstrated that CRKL promotes circCCDC50 biogenesis, which is transferred via oncosomes.
- Showed that nuclear circCCDC50 recruits CARM1 to epigenetically activate NFATc1, creating a self-sustaining loop.
- TP-064 effectively inhibited osteoclastogenesis and reduced bone metastasis in resistant models.
Conclusions:
- Discovered a novel, targetable mechanism of resistance to RANKL inhibitors in breast cancer bone metastasis.
- The CRKL/circCCDC50/NFATc1 axis represents a key driver of osteolysis in resistant disease.
- Pharmacological inhibition of CARM1 offers a promising therapeutic strategy to overcome denosumab resistance and target tumor-bone interactions.
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