Supplementary Figure 3 from hVps37A Status Affects Prognosis and Cetuximab Sensitivity in Ovarian Cancer
journal contribution
posted on 2023-03-31, 17:15 authored by Michael Wittinger, Petr Vanhara, Ahmed El-Gazzar, Bettina Savarese-Brenner, Dietmar Pils, Mariam Anees, Thomas W. Grunt, Maria Sibilia, Martin Holcmann, Reinhard Horvat, Michael Schemper, Robert Zeillinger, Christian Schöfer, Helmut Dolznig, Peter Horak, Michael KrainerPDF file - 229K
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ARTICLE ABSTRACT
Purpose: Although prognostic and predictive factors in ovarian cancer have been extensively studied for decades, only few have been identified and introduced to clinical practice. Here, we evaluate hVps37A (HCRP1) as a possible novel predictive marker for ovarian cancer. hVps37A was originally described as a member of the membrane-trafficking ESCRT-I complex mediating the internalization and degradation of ubiquitinated membrane receptors.Experimental Design: We analyzed an ovarian cancer tissue microarray for HCRP1, EGFR, and HER2 expression. We used a tetracycline inducible ovarian cancer cell culture model to show the effects of hVps37A knockdown in vitro and in vivo. In addition, we studied the effects of epidermal growth factor receptor (EGFR) inhibitors cetuximab and lapatinib on ovarian cancer cells under conditions of hVps37A knockdown.Results: We find that hVps37A is significantly downregulated in ovarian cancer and modifies the prognostic value of EGFR and HER2 expression. In addition, hVps37A downregulation in ovarian cancer cells leads to cytoplasmic pEGFR retention and hyperactivation of downstream pathways and is associated with enhanced xenograft growth in nude mice and invasion of the collagen matrix. Furthermore, due to subsequent sustained Akt- and MAPK-pathway activation, hVps37A-deficient cells become irresponsive to inhibition by the therapeutic antibody cetuximab.Conclusion: We propose that hVps37A status could become a novel prognostic and therapeutic marker for EGFR or HER2 driven tumors. Clin Cancer Res; 17(24); 7816–27. ©2011 AACR.Usage metrics
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Keywords
BiomarkersCell CycleSignal transduction pathwaysCell SignalingProtein tyrosine kinasesDrug ResistanceBiochemistry of membrane metabolism and transportDrug TargetsCell surface receptor drug targetsOncoprotein & tumor suppressor drug targetsProtein kinase & phosphatase drug targetsGynecological CancersOvarian cancerOncogenes & Tumor Suppressors
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