Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib Over Bevacizumab: Cell Cycle Abrogation and Synergy With Chemotherapy

Abstract

Background: Angiogenesis plays a crucial role in tumor development and metastasis, and several clinical trials of anti-angiogenic agents have been conducted in advanced and recurrent endometrial cancer. Both bevacizumab and cediranib have demonstrated activity as single agents, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our group has previously established that chemotherapy plus an angiokinase inhibitor promotes catastrophic cell death in a xenograft model of endometrial cancer. Our objective was to compare the efficacy of cediranib and bevacizumab in endometrial cancer models.Methods: The cellular effects of the bevacizumab and cediranib were examined in endometrial cancer cell lines using ERK phosphorylation, ligand shedding, cell viability and cell cycle progression as readouts. Cellular viability following exposure to bevacizumab or cediranib as single agents or in combination with chemotherapy was also tested in eight patient-derived organoid models of endometrial cancer. Finally, we performed a phosphoproteomic array of 875 phosphoproteins to define the signaling changes related to bevacizumab versus cediranib.Results: Whereas both bevacizumab and cediranib effectively blunted tyrosine kinase receptor signaling in human vascular endothelial cells, only cediranib blocked ligand-mediated ERK activation in endometrial cancer cells. In both cell lines and patient-derived organoid cultures, neither bevacizumab nor cediranib alone had a notable effect on cell viability, even at 1-10 µM concentrations. By contrast, cediranib but not bevacizumab promoted marked cell death when combined with chemotherapy. Cell cycle analysis demonstrated an accumulation in mitosis after treatment with cediranib+chemotherapy, consistent with abrogation of the G2/M checkpoint and subsequent mitotic catastrophe. Molecular analysis of key controllers of the G2/M cell cycle checkpoint confirmed its abrogation. Phosphoproteomic analysis revealed that bevacizumab and cediranib had both similar and unique effects on cell signaling that underlie their shared versus individual actions as anti-angiogenic agents. Conclusions: Based on these data, we conclude that an anti-angiogenic tyrosine kinase inhibitor such as cediranib has the potential to be superior to bevacizumab in combination with chemotherapy. These data set the stage for future clinical studies of the combination of standard chemotherapy with cediranib in advanced and recurrent endometrial cancer.

Comparison of afatinib and erlotinib combined with bevacizumab in untreated stage IIIB/IV epidermal growth factor receptor-mutated lung adenocarcinoma patients: a multicenter clinical analysis study

“…Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). 11,12 A previous preclinical study demonstrated that plasma VEGF and tumor VEGF mRNA levels increased after erlotinib treatment in an NSCLC xenograft murine model. Increasing VEGF levels in tumors and plasma are associated with tumor progression and erlotinib resistance in an NSCLC xenograft murine model.…”