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Autocrine down-regulation of basic fibroblast growth factor receptors causes mitotoxin resistance in a human melanoma
P Davol1, J G Beitz, A R Frackelton
1Department of Medicine, Roger Williams Medical Center, Providence, RI 02908, USA.
Abstract:
The ability of melanoma to develop resistance to mitotoxins, growth-factor-directed anti-neoplastic agents that offer potential for the treatment of this highly refractory disease, may limit therapeutic efficacy. To address this problem, we developed a subcloned human melanoma cell line that is resistant to the mitotoxin composed of basic fibroblast growth factor conjugated to the ribosome-inactivating protein saporin. Resistance was caused by autocrine FGF ligands, which down-regulate bFGF receptors and reduce bFGF-saporin binding. Inhibiting the autocrine loop with suramin or with neutralizing antibodies to FGF up-regulated receptors and decreased resistance in vitro. Furthermore, suramin restored sensitivity in resistant tumor xenografts. These results suggest the potential of therapeutic modalities combining agents that neutralize growth factors with receptor-directed mitotoxins for targeting malignant melanoma either to prevent emergence of resistance or to circumvent resistance once it occurs.
Insights
Melanoma resistance to growth factor toxins can be overcome. Inhibiting autocrine loops with suramin or antibodies re-sensitized resistant melanoma cells and tumors to treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Melanoma can develop resistance to mitotoxins, limiting treatment efficacy.
- Mitotoxins targeting growth factor receptors are a potential therapy for refractory melanoma.
Purpose of the Study:
- To develop and characterize a human melanoma cell line resistant to basic fibroblast growth factor-saporin (bFGF-saporin) mitotoxin.
- To investigate mechanisms of resistance and strategies to overcome it.
Main Methods:
- Developed a subcloned human melanoma cell line resistant to bFGF-saporin.
- Investigated the role of autocrine FGF ligands in resistance.
- Tested suramin and neutralizing antibodies against FGF to reverse resistance in vitro and in vivo.
Main Results:
- Resistance was mediated by autocrine FGF ligands down-regulating bFGF receptors.
- Suramin and anti-FGF antibodies increased receptor expression and reduced resistance in vitro.
- Suramin restored sensitivity in resistant melanoma xenografts.
Conclusions:
- Autocrine FGF signaling drives resistance to bFGF-saporin in melanoma.
- Combining growth factor neutralization with receptor-targeted mitotoxins may overcome or prevent resistance.
- This strategy holds promise for treating malignant melanoma.