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Inhibition of Activated Fibroblast Growth Factor Receptor 2 in Endometrial Cancer Cells Induces Cell Death Despite PTEN Abrogation

¹ Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona and Departments of ² Obstetrics and Gynecology and ³ Surgery, Washington University School of Medicine, St. Louis, Missouri

Requests for reprints: Pamela M. Pollock, Translational Genomics Research Institute, 445 North 5th Street, Phoenix, AZ 85004. Phone: 602-343-8815; Fax: 602-343-8840; E-mail: ppollock{at}tgen.org.

Key Words: endometrial cancer • molecular-targeted therapy • FGFR2 • PTEN • MAPK

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type. [Cancer Res 2008;68(17):6902–7]

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				S. Ota, Z.-Q. Zhou, J. M. Link, and P. J. Hurlin The role of senescence and prosurvival signaling in controlling the oncogenic activity of FGFR2 mutants associated with cancer and birth defects Hum. Mol. Genet., July 15, 2009; 18(14): 2609 - 2621. [Abstract] [Full Text] [PDF]

				Correction: Inhibition of Activated FGFR2 in Endometrial Cancer Cancer Res., December 1, 2008; 68(23): 10005 - 10005. [Full Text] [PDF]