The central role of a two‐way positive feedback pathway in molecular targeted therapies‐mediated pyroptosis in anaplastic thyroid cancer

作者：Qiwu Zhao, Haoran Feng, Zheyu Yang, Juyong Liang, Zhijian Jin, Lingxie Chen, Ling Zhan, Ming Xuan, Jiqi Yan, Jie Kuang, Xi Cheng, Ren Zhao, Weihua Qiu · 发表于：Clinical and Translational Medicine · 年份：2022 · DOI：10.1002/ctm2.727 · 被引用次数：48 · 研究领域：Inflammasome and immune disorders、Cell death mechanisms and regulation、Thyroid Cancer Diagnosis and Treatment

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive tumours. We previously confirmed that apatinib has potential therapeutic effects on ATC via regulated cell death (RCD). As a newly identified RCD, pyroptosis demonstrates direct antitumour activity different from apoptosis or autophagy. Therefore, the clinical significance, regulatory role and underlying mechanisms of pyroptosis in ATC were focused on in this study. METHODS: In a phase II trial, patients with anaplastic or poorly differentiated thyroid carcinoma received apatinib 500 mg once daily. Multiple assays were implemented to evaluate the antitumour efficacy of apatinib and/or melittin in vitro and in vivo. High-throughput sequencing was applied to analyse differential mRNAs expression in ATC cells treated by apatinib with or without melittin. In situ Hoechst 33342/PI double-staining, LDH release assay and enzyme-linked immunosorbent assay (ELISA) were employed to determine pyroptosis. In mechanism exploration, quantitative RT-PCR, Western blotting and si-RNA knocking down were executed. RESULTS: Seventeen patients were evaluable. Apatinib showed a promising therapeutic effect by a disease control rate (DCR) of 88.2%; however, treatment was terminated in 23.5% of patients due to intolerable toxicity. To reduce adverse events, a pyroptosis-mediated synergistic antitumour effect of apatinib and melittin was identified in treatment of ATC in vitro and in vivo. The caspase-1-gasdermin D (GSDMD) a...