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Targeting Focal Adhesion Kinase Suppresses the Malignant Phenotype in Rhabdomyosarcoma Cells
Alicia M Waters1, Laura L Stafman1, Evan F Garner1
1Department of Surgery, Division of Pediatric Surgery, University of Alabama, Birmingham, AL.
Abstract:
Despite the tremendous advances in the treatment of childhood solid tumors, rhabdomyosarcoma (RMS) continues to provide a therapeutic challenge. Children with metastatic or relapsed disease have a disease-free survival rate under 30%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumorigenesis. Signaling pathways both upstream and downstream to FAK have been found to be important in sarcoma tumorigenesis, leading us to hypothesize that FAK would be present in RMS and would impact cellular survival. In the current study, we showed that FAK was present and phosphorylated in pediatric alveolar and embryonal RMS tumor specimens and cell lines. We also examined the effects of FAK inhibition upon two RMS cell lines utilizing parallel approaches including RNAi and small molecule inhibitors. FAK inhibition resulted in decreased cellular survival, invasion, and migration and increased apoptosis. Furthermore, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse RMS xenograft model. The findings from this study will help to further our understanding of the regulation of tumorigenesis in RMS and may provide desperately needed novel therapeutic strategies for these difficult-to-treat tumors.
Insights
Focal adhesion kinase (FAK) inhibition significantly reduced rhabdomyosarcoma (RMS) growth, invasion, and migration while increasing apoptosis. This study highlights FAK as a potential therapeutic target for challenging pediatric RMS tumors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Rhabdomyosarcoma (RMS) remains a significant therapeutic challenge in pediatric oncology, particularly for metastatic or relapsed cases.
- Focal adhesion kinase (FAK), a nonreceptor tyrosine kinase, plays a crucial role in various aspects of tumorigenesis, including sarcoma development.
Purpose of the Study:
- To investigate the presence and role of FAK in pediatric RMS.
- To evaluate the therapeutic potential of FAK inhibition in RMS.
Main Methods:
- Analysis of FAK expression and phosphorylation in RMS tumor specimens and cell lines.
- Inhibition of FAK using RNA interference (RNAi) and small molecule inhibitors in RMS cell lines.
- Assessment of cellular survival, invasion, migration, and apoptosis following FAK inhibition.
- Evaluation of FAK inhibition on RMS tumor growth in a xenograft mouse model.
Main Results:
- FAK was found to be present and phosphorylated in pediatric RMS tumor samples and cell lines.
- FAK inhibition led to reduced cellular survival, invasion, and migration.
- FAK inhibition significantly increased apoptosis in RMS cells.
- Small molecule inhibition of FAK suppressed tumor growth in an RMS xenograft model.
Conclusions:
- FAK is present and active in RMS, contributing to tumor progression.
- Targeting FAK demonstrates therapeutic promise for treating pediatric RMS.
- FAK inhibition offers a potential novel strategy for difficult-to-treat RMS.
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