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Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
Published on: October 5, 2020
Sodium cantharidate targets STAT3 and abrogates EGFR inhibitor resistance in osteosarcoma
1Department of Orthopedic Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
Abstract:
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Overactive EGFR signaling is frequently seen in osteosarcoma cells, and represents a potential therapeutic target. However, feedback activation of STAT3 after EGFR inhibition is linked to treatment resistance, suggesting that combined EGFR/STAT3 inhibition may be needed to overcome this effect. Cantharidin and its analogues have shown strong anticancer effects, including STAT3 inhibition, in several tumor cells. Therefore, we investigated the effects of sodium cantharidate (SC), either as monotherapy and in combination with the EGFR inhibitor erlotinib, on STAT3 activation and osteosarcoma cell growth. Cell viability, migration, and apoptosis assays were performed in human MG63 and U2OS cells, and MG63 xenografts were generated in nude mice to verify the suppression of tumor growth in vivo. Additionally, western blotting and immunohistochemistry were used to verify the STAT3 and EGFR phosphorylation statuses in xenografts. We found that SC repressed cell viability and migration and induced apoptosis in vitro, while combined SC and erlotinib treatment enhanced osteosarcoma growth suppression by preventing feedback activation of STAT3. These data support further development of cantharidin-based combination therapies for metastatic and recurrent/refractory osteosarcoma.
Insights
Sodium cantharidate (SC) and erlotinib combination therapy shows promise for osteosarcoma treatment. This approach inhibits both EGFR and STAT3 signaling, overcoming resistance and suppressing tumor growth in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osteosarcoma is the most common primary bone cancer in children and adolescents.
- Overactive Epidermal Growth Factor Receptor (EGFR) signaling is a hallmark of osteosarcoma, presenting a therapeutic target.
- Feedback activation of Signal Transducer and Activator of Transcription 3 (STAT3) following EGFR inhibition leads to treatment resistance.
Purpose of the Study:
- To investigate the efficacy of sodium cantharidate (SC), a STAT3 inhibitor, as monotherapy and in combination with erlotinib, an EGFR inhibitor.
- To evaluate the impact of this combination on osteosarcoma cell growth, STAT3 activation, and in vivo tumor suppression.
Main Methods:
- In vitro assays: cell viability, migration, and apoptosis in human osteosarcoma cell lines (MG63, U2OS).
- In vivo studies: MG63 xenografts in nude mice.
- Molecular analysis: Western blotting and immunohistochemistry to assess EGFR and STAT3 phosphorylation.
Main Results:
- Sodium cantharidate (SC) monotherapy inhibited osteosarcoma cell viability and migration while inducing apoptosis in vitro.
- Combined SC and erlotinib treatment demonstrated enhanced osteosarcoma growth suppression compared to monotherapy.
- The combination therapy prevented feedback activation of STAT3, a key mechanism for overcoming resistance.
Conclusions:
- Sodium cantharidate (SC) exhibits anticancer properties and can inhibit STAT3 activation.
- Combination therapy with SC and erlotinib is a promising strategy to overcome EGFR-mediated treatment resistance in osteosarcoma.
- These findings support the further development of cantharidin-based combination therapies for metastatic and refractory osteosarcoma.
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