Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression
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Updated: Mar 28, 2026
Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
Published on: October 28, 2021
Benjamin Ory1, Marc Baud'huin2, Franck Verrecchia1
1Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France.
Purpose:
Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among them, HSP90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival and disease progression. We assessed the antitumor properties of a synthetic HSP90 inhibitor, PF4942847, alone or in combination with zoledronic acid in osteosarcoma.
Experimental Design:
The effects of PF4942847 were evaluated on human osteosarcoma cells growth and apoptosis. Signaling pathways were analyzed by Western blotting. The consequence of HSP90 therapy combined or not with zoledronic acid was evaluated in mice bearing HOS-MNNG xenografts on tumor growth, associated bone lesions, and pulmonary metastasis. The effect of PF4942847 on osteoclastogenesis was assessed on human CD14(+) monocytes.
Results:
In osteosarcoma cell lines, PF4942847 inhibited cell growth in a dose-dependent manner (IC50 ±50 nmol/L) and induced apoptosis with an increase of sub-G1 fraction and cleaved PARP. These biologic events were accompanied by decreased expression of Akt, p-ERK, c-Met, and c-RAF1. When administered orally to mice bearing osteosarcoma tumors, PF4942847 significantly inhibited tumor growth by 80%, prolonged survival compared with controls, and inhibited pulmonary metastases by blocking c-Met, FAK, and MMP9 signaling. In contrast to 17-allylamino-17-demethoxygeldanamycin (17-AAG), PF4942847 did not induce osteoclast differentiation, and synergistically acted with zoledronic acid to delay osteosarcoma progression and prevent bone lesions.
Conclusions:
All these data provide a strong rationale for clinical evaluation of PF4942847 alone or in combination with zoledronic acid in osteosarcoma. Clin Cancer Res; 22(10); 2520-33. ©2015 AACR.
Insights
A novel HSP90 inhibitor, PF4942847, effectively reduced osteosarcoma growth and metastasis in preclinical models. Combining PF4942847 with zoledronic acid showed synergistic effects, delaying tumor progression and bone lesions.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osteosarcoma treatment faces challenges with chemotherapy response, necessitating novel therapeutic strategies.
- Heat Shock Protein 90 (HSP90) is a molecular chaperone crucial for oncogenic protein stability, promoting tumor cell survival and disease progression.
- Targeting HSP90 presents a promising avenue for improving osteosarcoma patient outcomes.
Purpose of the Study:
- To evaluate the antitumor properties of the synthetic HSP90 inhibitor PF4942847.
- To assess the efficacy of PF4942847 alone and in combination with zoledronic acid in osteosarcoma.
- To investigate the impact of PF4942847 on cancer cell signaling pathways and osteoclastogenesis.
Main Methods:
- In vitro assessment of PF4942847 effects on human osteosarcoma cell growth and apoptosis, with signaling pathway analysis via Western blotting.
- In vivo evaluation of PF4942847, alone or with zoledronic acid, in mice bearing osteosarcoma xenografts, monitoring tumor growth, bone lesions, and pulmonary metastasis.
- Assessment of PF4942847's effect on human monocyte-derived osteoclastogenesis.
Main Results:
- PF4942847 inhibited osteosarcoma cell growth dose-dependently (IC50 ±50 nmol/L) and induced apoptosis, decreasing Akt, p-ERK, c-Met, and c-RAF1 expression.
- In vivo, PF4942847 significantly inhibited tumor growth (80%), prolonged survival, and reduced pulmonary metastases by targeting c-Met, FAK, and MMP9 signaling.
- PF4942847 did not induce osteoclast differentiation and synergized with zoledronic acid to delay tumor progression and prevent bone lesions.
Conclusions:
- PF4942847 demonstrates significant preclinical efficacy against osteosarcoma, both as a single agent and in combination with zoledronic acid.
- The findings support the clinical evaluation of PF4942847 in osteosarcoma treatment strategies.
- Targeting HSP90 offers a viable approach to overcome therapeutic resistance and improve patient survival in osteosarcoma.
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