AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1
| Autor: | Ruing Zhao, Shenglin Ma, Qinghua Deng, Ke Zhang, Yanjiao Mao, Qingqing Yu, Wei Yin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Lung Neoplasms
Applied Microbiology and Biotechnology Tyrosine-kinase inhibitor Receptor tyrosine kinase Piperazines Mice egfr mutant Carcinoma Non-Small-Cell Lung Medicine Osimertinib Epidermal growth factor receptor Aniline Compounds Janus kinase 1 biology Brain Neoplasms jak1 Cell Cycle General Medicine Chemoradiotherapy ErbB Receptors Gene Expression Regulation Neoplastic osimertinib azd3759 medicine.drug Research Article Research Paper Biotechnology medicine.drug_class Cell Survival Mice Nude Bioengineering Gefitinib Cell Line Tumor Animals Humans Lung cancer Cell Proliferation Acrylamides business.industry Janus Kinase 1 medicine.disease Xenograft Model Antitumor Assays respiratory tract diseases Apoptosis Cancer research biology.protein Quinazolines business nsclc TP248.13-248.65 |
| Zdroj: | Bioengineered, Vol 13, Iss 1, Pp 331-344 (2022) Bioengineered article-version (VoR) Version of Record |
| ISSN: | 2165-5987 2165-5979 |
| Popis: | AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical trials, the regulatory effects of this inhibitor on the antitumor efficacy of radiation (RA) are unclear. The present study aimed to compare the effects of AZD3759 and osimertinib on RA efficacy in NSCLC and explore the potential mechanism of action of AZD3759. We found that the survival in RA-treated NSCLC cells was significantly decreased by treatment with 500 nM AZD3759 and osimertinib at the RA dosage of 8 Gy. The apoptotic rate, cell cycle arrest, and DNA damage in RA-treated NSCLC cells and brain metastasis in RA-treated xenograft nude mice were significantly enhanced by the co-administration of AZD3759 and osimertinib, respectively. In addition, AZD3759 showed a significantly stronger efficacy than osimertinib did. Mechanistically, the receptor tyrosine kinase signaling antibody array revealed that Janus kinase-1 (JAK1) was specifically inhibited by AZD3759, but not by osimertinib. The effects of AZD3759 on RA efficacy in PC-9 cells and in a brain metastasis animal model were significantly abolished by the overexpression of JAK1. Collectively, our results suggested that AZD3759 promoted RA antitumor effects in NSCLC by synergistic blockade of EGFR and JAK1. |
| Databáze: | OpenAIRE |
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