Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR‑mutant lung cancer with HIF‑1α/TGF‑α expression

Nishii,Kazuya; Ohashi,Kadoaki; Watanabe,Hiromi; Makimoto,Go; Nakasuka,Takamasa; Higo,Hisao; Ninomiya,Kiichiro; Kato,Yuka; Kubo,Toshio; Rai,Kammei; Ichihara,Eiki; Hotta,Katsuyuki; Tabata,Masahiro; Maeda,Yoshinobu; Kiura,Katsuyuki

doi:10.3892/ol.2021.12900

Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR‑mutant lung cancer with HIF‑1α/TGF‑α expression

Authors:
- Kazuya Nishii
- Kadoaki Ohashi
- Hiromi Watanabe
- Go Makimoto
- Takamasa Nakasuka
- Hisao Higo
- Kiichiro Ninomiya
- Yuka Kato
- Toshio Kubo
- Kammei Rai
- Eiki Ichihara
- Katsuyuki Hotta
- Masahiro Tabata
- Yoshinobu Maeda
- Katsuyuki Kiura
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Affiliations: Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8558, Japan, Department of Respiratory Medicine, Okayama University Hospital, Okayama 700‑8558, Japan, Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700‑8558, Japan, Center for Clinical Oncology, Okayama University Hospital, Okayama 700‑8558, Japan
Published online on: July 7, 2021 https://doi.org/10.3892/ol.2021.12900
Article Number: 639
Copyright: © Nishii et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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