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Updated: Jul 14, 2026
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Published on: October 27, 2020
Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats
Nicholas J Laping1, Jeffrey I Everitt, Kendall S Frazier
1GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Purpose:
Transforming growth factor beta (TGF-beta), which generally stimulates the growth of mesenchymally derived cells but inhibits the growth of epithelial cells, has been proposed as a possible target for cancer therapy. However, concerns have been raised that whereas inhibition of TGF-beta signaling could be efficacious for lesions in which TGF-beta promotes tumor development and/or progression, systemic pharmacologic blockade of this signaling pathway could also promote the growth of epithelial lesions.
Experimental Design:
We examined the effect of a TGF-beta inhibitor on mesenchymal (leiomyoma) and epithelial (renal cell carcinoma) tumors in Eker rats, which are genetically predisposed to develop these tumors with a high frequency.
Results:
Blockade of TGF-beta signaling with the ALK5/type I TGF-beta R kinase inhibitor, SB-525334, was efficacious for uterine leiomyoma; significantly decreasing tumor incidence and multiplicity, and reducing the size of these mesenchymal tumors. However, SB-525334 was also mitogenic and antiapoptotic for epithelial cells in the kidney and exacerbated the growth of epithelial lesions present in the kidneys of these animals.
Conclusion:
Although pharmacologic inhibition of TGF-beta signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors.
Insights
Pharmacologic inhibition of transforming growth factor beta (TGF-beta) signaling effectively treated mesenchymal tumors but promoted epithelial tumor growth in rats. This highlights the dual role of TGF-beta in cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Transforming growth factor beta (TGF-beta) differentially affects mesenchymal and epithelial cell growth.
- TGF-beta signaling is a potential target for cancer therapy, but its dual role presents challenges.
- Concerns exist that systemic blockade of TGF-beta could promote epithelial lesions.
Purpose of the Study:
- To investigate the effect of a TGF-beta inhibitor on mesenchymal and epithelial tumors.
- To evaluate the therapeutic potential and risks of TGF-beta pathway blockade in cancer.
Main Methods:
- Utilized Eker rats, genetically predisposed to mesenchymal (leiomyoma) and epithelial (renal cell carcinoma) tumors.
- Administered SB-525334, an ALK5/type I TGF-beta receptor kinase inhibitor, to assess its impact on tumor development.
- Examined tumor incidence, multiplicity, size, and cellular proliferation/apoptosis.
Main Results:
- SB-525334 significantly reduced the incidence, multiplicity, and size of mesenchymal uterine leiomyomas.
- The TGF-beta inhibitor SB-525334 exhibited mitogenic and antiapoptotic effects on epithelial cells.
- SB-525334 exacerbated the growth of existing epithelial lesions in the kidneys.
Conclusions:
- Pharmacologic inhibition of TGF-beta signaling with SB-525334 demonstrates efficacy against mesenchymal tumors.
- Inhibition of TGF-beta signaling appears to promote the development and progression of epithelial tumors.
- The findings suggest a context-dependent role for TGF-beta inhibition in cancer therapy, necessitating careful consideration of tumor cell type.
