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

Abstract

Angiogenesis plays a crucial role in tumor development and metastasis. Both bevacizumab and cediranib have demonstrated activity as single anti-angiogenic agents in endometrial cancer, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our objective was to compare the efficacy of cediranib and bevacizumab in endometrial cancer models. The cellular effects of bevacizumab and cediranib were examined in endometrial cancer cell lines using extracellular signal-related kinase (ERK) phosphorylation, ligand shedding, cell viability, and cell cycle progression as readouts. Cellular viability 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. Cediranib but not bevacizumab blocked ligand-mediated ERK activation in endometrial cancer cells. In both cell lines and patient-derived organoids, neither bevacizumab nor cediranib alone had a notable effect on cell viability. 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 the 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. An anti-angiogenic tyrosine kinase inhibitor such as cediranib has the potential to be superior to bevacizumab in combination with chemotherapy.

Vitamin D Enhances Anticancer Properties of Cediranib, a VEGFR Inhibitor, by Modulation of VEGFR2 Expression in Melanoma Cells

“…We have shown that supplementation with vitamin D improves the effectiveness of anti-angiogenic compound, cediranib, against A375 and SK-MEL-28 human melanoma cells, as we observed a marked decrease in melanoma cell proliferation (in both lines), G2/M cell cycle arrest, and a significant decrease in melanoma cell mobility (tested only in A375 melanoma cells). A similar observation was recently described in Hec50 cells, an endometrial adenocarcinoma, in which the combination of paclitaxel and cediranib produced a profound increase in the accumulation of cells in mitosis as assessed by the percentage of cells in G2/M by flow cytometry compared to paclitaxel alone (75). On the other hand, we did not observe any influence of vitamin D on proliferation of MNT-1 and RPMI-7951 melanoma cells treated with cediranib.…”

“…Still, the authors concluded that the potential of cediranib may be enhanced in combination with other agents (68). Furthermore, it was shown recently on patient-derived organoid models of endometrial cancer that cediranib but not bevacizumab synergizes with chemotherapy, decreasing cell viability when combined with paclitaxel as compared to treatment with paclitaxel alone (75). Currently, there is an ongoing phase I clinical trial, NCT01364051, for patients with clinically unresectable solid tumors, including stage IV cutaneous melanoma and malignant melanoma, and for whom there is no standard therapy, in which patients are receiving cediranib with selumetinib, an oral MEK 1/2 inhibitor.…”

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.…”

The mechanistic immunosuppressive role of the tumour vasculature and potential nanoparticle-mediated therapeutic strategies

“…Inhibition of multiple RTKs is an advantageous feature in cancer treatment. A study by Bi et al, 2021 has shown that cediranib combination with paclitaxel had higher cell death while bevacizumab combination with paclitaxel treatment showing a small insignificant change in cell death in endometrial cancer cells (102). In phase III trials, cediranib had limited benefit in metastatic colorectal cancer (NCT00384176), non-small cell lung cancer (NCT00795340), and recurrent glioblastoma (NCT00777153) (117)(118)(119).…”

“…Furthermore, combining bevacizumab with various chemotherapies (paclitaxel and ixabepilone) in patients with TP53 mutations improved PFS and OS compared to chemotherapy alone ( 101 ). However, cediranib, an anti-angiogenic tyrosine kinase inhibitor, demonstrated higher cell cycle abrogation and synergy with chemotherapy compared to bevacizumab in endometrial cancer models in vitro ( 102 ).…”