Effects of bevacizumab in mouse model of endometrial cancer: Defining the molecular basis for resistance.
Endometrial cancer is the most frequent gynecologic cancer in women. Long-term outcomes for patients with advanced stage or recurrent disease are poor. Targeted molecular therapy against the vascular endothelial growth factor (VEGF) and its receptors constitute a new therapeutic option for these patients. The goal of our study was to assess the potential effectiveness of inhibition of VEGF/VEGFR signaling in a xenograft model of endometrial cancer using bevacizumab (Avastin, a humanized antibody against VEGFA). We also aimed to identify molecular markers of sensitivity or resistance to this agent. We show that bevacizumab retards tumor growth in athymic mice by inhibiting molecular components of signaling pathways that sustain cell survival and proliferation. We also demonstrate that resistance to bevacizumab may involve up-regulation of anti-apoptotic genes and certain proto-oncogenes. We propose that down-regulation of ARHGAP6 and MMP15 transcripts indicates that tumors are sensitive to bevacizumab whereas inhibition of PKCδ- or S6K-dependent signaling and up-regulation of TNFRS4 or MMP13 and MMP14 mark a developing resistance to bevacizumab therapy. Interestingly, the significant activation of c-Jun oncogene detected in bevacizumab-treated tumors suggests that, in endometrial cancers, the c-Jun-mediated pathway(s) contribute to bevacizumab resistance.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Suzy
S
Davies
Donghai
D
Dai
Gavin
G
Pickett
Kristina W
KW
Thiel
Victoria P
VP
Korovkina
Kimberly K
KK
Leslie
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D005260:Female; D051379:Mice; D008819:Mice, Nude; D047368:Tumor Burden / Q000187:drug effects; D054928:Validation Studies as Topic; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab
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