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Anlotinib inhibits synovial sarcoma by targeting GINS1: a novel downstream target oncogene in progression of synovial
1Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, No. 600, Yishan Road, Xuhui District, Shanghai, 200233, People's Republic of China.
Background:
Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma with a poor prognosis owing to its resistance to radiation and chemotherapy. Thus, novel therapeutic strategies for SS are urgently required. Anlotinib, a new oral tyrosine kinase inhibitor, is designed to primarily inhibit multi-targets in vasculogenesis and angiogenesis. This study was designed to characterize its antitumor efficacy and possible mechanism in patients with advanced refractory synovial sarcoma.
Methods:
Anlotinib's antitumor effect was evaluated in vivo and vitro. Downstream targets of anlotinib in treating synovial sarcoma were analyzed through microarray assay. Cell proliferation and apoptosis analyses were performed to evaluate the impact of candidate downstream gene depletion in synovial sarcoma cells. Microarray assay were carried out to investigate potential signal network related with candidate downstream gene.
Results:
Anlotinib significantly suppresses synovial sarcoma proliferation in PDTX model and cell lines. Additionally, GINS1 (also named as PSF1, Partner of SLD Five 1), rather than other conventional gene target, was demonstrated to be a vital target of anlotinib's antitumor effect in synovial sarcoma through microarray assay. Expression of GINS1 was remarkably higher in synovial sarcoma tumor samples and related with poor outcome. Knockdown of GINS1 expression could remarkably inhibit proliferation and promote apoptosis in vitro. Meanwhile, through microarray assay, CITED2, EGR1, SGK1 and SPP1 were identified and further validated by qPCR/WB as downstream targets of GINS1.
Conclusion:
Anlotinib might suppress proliferation of SS through a novel downstream GINS1-regulated network which plays a vital function in SS proliferation and also demonstrated that targeting the GINS1-regulated signal pathway could be a potential strategy for management of SS.
Insights
Anlotinib shows promise in treating synovial sarcoma (SS) by inhibiting GINS1, a key driver of tumor growth. Targeting this GINS1 network may offer a new therapeutic strategy for advanced SS.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Synovial sarcoma (SS) is an aggressive soft-tissue cancer with poor outcomes due to treatment resistance.
- Novel therapeutic strategies are crucial for advanced and refractory SS.
- Anlotinib, a multi-target tyrosine kinase inhibitor, targets vasculogenesis and angiogenesis.
Purpose of the Study:
- To evaluate the antitumor efficacy of anlotinib in advanced refractory synovial sarcoma.
- To elucidate the underlying molecular mechanisms of anlotinib's action in SS.
- To identify novel therapeutic targets within the SS signaling network.
Main Methods:
- In vitro and in vivo evaluation of anlotinib's antitumor effects.
- Microarray analysis to identify anlotinib's downstream targets in SS.
- Gene depletion studies to assess the impact of candidate targets on SS cell proliferation and apoptosis.
Main Results:
- Anlotinib significantly inhibited synovial sarcoma proliferation in preclinical models.
- GINS1 was identified as a critical downstream target of anlotinib in SS, distinct from conventional targets.
- Elevated GINS1 expression correlated with poor prognosis in SS patients, and its knockdown suppressed tumor growth and induced apoptosis.
- CITED2, EGR1, SGK1, and SPP1 were validated as downstream targets of GINS1.
Conclusions:
- Anlotinib suppresses SS proliferation via a novel GINS1-regulated network.
- GINS1 plays a vital role in SS proliferation.
- Targeting the GINS1 signaling pathway presents a potential therapeutic strategy for SS management.
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