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FGFR2 as a molecular target in endometrial cancer
Sara A Byron1, Pamela M Pollock
1Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
Abstract:
Although molecularly targeted therapies have been effective in some cancer types, no targeted therapy is approved for use in endometrial cancer. The recent identification of activating mutations in fibroblast growth factor receptor 2 (FGFR2) in endometrial tumors has generated a new avenue for the development of targeted therapeutic agents. The majority of the mutations identified are identical to germline mutations in FGFR2 and FGFR3 that cause craniosynostosis and hypochondroplasia syndromes and result in both ligand-independent and ligand-dependent receptor activation. Mutations that predominantly occur in the endometrioid subtype of endometrial cancer, are mutually exclusive with KRAS mutation, but occur in the presence of PTEN abrogation. In vitro studies have shown that endometrial cancer cell lines with activating FGFR2 mutations are selectively sensitive to a pan-FGFR inhibitor, PD173074. Several agents with activity against FGFRs are currently in clinical trials. Investigation of these agents in endometrial cancer patients with activating FGFR2 mutations is warranted.
Insights
Activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer offer a new target for therapy. Cancer cells with these FGFR2 mutations show sensitivity to FGFR inhibitors, suggesting a potential new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- No targeted therapies are currently approved for endometrial cancer.
- Activating mutations in fibroblast growth factor receptor 2 (FGFR2) have been identified in endometrial tumors.
- These FGFR2 mutations are similar to those causing developmental syndromes and lead to receptor overactivation.
Purpose of the Study:
- To explore the therapeutic potential of targeting FGFR2 in endometrial cancer.
- To investigate the role of FGFR2 mutations in endometrial cancer development and treatment sensitivity.
Main Methods:
- Analysis of FGFR2 mutations in endometrial tumors.
- In vitro studies using endometrial cancer cell lines with FGFR2 mutations.
- Testing sensitivity to a pan-FGFR inhibitor (PD173074).
Main Results:
- Activating FGFR2 mutations were identified in endometrial cancer, predominantly in the endometrioid subtype.
- These mutations were mutually exclusive with KRAS mutations but occurred with PTEN abrogation.
- Endometrial cancer cell lines with FGFR2 mutations demonstrated selective sensitivity to the FGFR inhibitor PD173074.
Conclusions:
- Activating FGFR2 mutations represent a promising therapeutic target for endometrial cancer.
- FGFR inhibitors warrant investigation in clinical trials for patients with activating FGFR2 mutations in endometrial cancer.
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