Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR‑mutant lung cancer with HIF‑1α/TGF‑α expression
| Autor: | Eiki Ichihara, Toshio Kubo, Kiichiro Ninomiya, Hisao Higo, Katsuyuki Kiura, Kazuya Nishii, Go Makimoto, Kammei Rai, Hiromi Watanabe, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Takamasa Nakasuka, Yuka Kato |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Bevacizumab Combination therapy medicine.drug_class bevacizumab Tyrosine-kinase inhibitor transforming growth factor‑α cetuximab medicine Osimertinib Epidermal growth factor receptor Lung cancer hypoxia-inducible factor-1α Cetuximab biology business.industry Cancer Articles medicine.disease transforming growth factor-α hypoxia‑inducible factor‑1α Oncology osimertinib Cancer research biology.protein epidermal growth factor receptor business medicine.drug |
| Zdroj: | Oncology Letters |
| ISSN: | 1792-1082 1792-1074 |
| DOI: | 10.3892/ol.2021.12900 |
| Popis: | Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm3 and large model, 500 mm3). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-α (TGF-α) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF-α attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF-1α/TGF-α. |
| Databáze: | OpenAIRE |
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