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Updated: May 2, 2026
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Transglutaminase 2 inhibitor abrogates renal cell carcinoma in xenograft models
Bo Mi Ku1, Se-Jin Kim, Nayeon Kim
1Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Republic of Korea.
Purpose:
To test whether transglutaminase 2 (TGase 2) inhibitor GK921 alone reverses renal cell carcinoma (RCC) tumor growth. RCC is resistant to both radiation and chemotherapy, and the prognosis remains poor. Despite the recent therapeutic success of vascular endothelial growth factor inhibition in RCC, approximately one-third of RCC patients develop metastatic disease. The expression of TGase 2 is markedly increased in most RCC cell lines, as well as in clinical samples.
Methods:
Previously, we introduced the quinoxaline derivative GK13 as a lead compound for TGase 2 inhibitor. The inhibitory effect of GK13 on TGase 2 was improved in GK921 (3-(phenylethynyl)-2-(2-(pyridin-2-yl)ethoxy)pyrido[3,2-b]pyrazine). GK921 efficacy was tested using sulforhodamine in vitro as well as a xenograft tumor models using ACHN and CAKI-1 RCC cells.
Results:
GK921 showed cytotoxicity to RCC (average GI50 in eight RCC cell lines: 0.905 μM). A single treatment with GK921 almost completely reduced tumor growth by stabilizing p53 in the ACHN and CAKI-1 preclinical xenograft tumor models.
Conclusion:
TGase 2 inhibitor GK921 abrogates RCC growth in xenograft tumor models, suggesting the possibility of a new therapeutic approach to RCC.
Insights
Transglutaminase 2 (TGase 2) inhibitor GK921 effectively halts renal cell carcinoma (RCC) tumor growth. This novel TGase 2 inhibitor shows promise as a new therapeutic strategy for treating resistant RCC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Renal cell carcinoma (RCC) exhibits resistance to conventional treatments, leading to poor prognoses.
- Despite advancements like VEGF inhibition, metastatic disease remains a challenge in approximately one-third of RCC patients.
- Transglutaminase 2 (TGase 2) expression is significantly elevated in RCC cell lines and clinical samples.
Purpose of the Study:
- To evaluate the efficacy of TGase 2 inhibitor GK921 in reversing renal cell carcinoma (RCC) tumor growth.
- To determine if GK921 can serve as a standalone therapeutic agent for RCC.
Main Methods:
- GK921, a novel quinoxaline derivative, was developed as an improved TGase 2 inhibitor.
- In vitro cytotoxicity was assessed using sulforhodamine assays across eight RCC cell lines.
- In vivo efficacy was evaluated using preclinical xenograft tumor models with ACHN and CAKI-1 RCC cells.
Main Results:
- GK921 demonstrated significant cytotoxicity against RCC cell lines, with an average GI50 of 0.905 μM.
- A single administration of GK921 substantially inhibited tumor growth in xenograft models.
- Tumor growth reduction was associated with the stabilization of p53.
Conclusions:
- The TGase 2 inhibitor GK921 effectively abrogates RCC growth in preclinical xenograft models.
- These findings suggest GK921 as a potential novel therapeutic agent for renal cell carcinoma.
- Targeting TGase 2 represents a promising new strategy for RCC treatment.
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