头颈部鳞状细胞癌
癌症研究
自噬
车站3
医学
信号转导
表皮生长因子受体抑制剂
表皮生长因子受体
癌症
细胞凋亡
头颈部癌
生物
内科学
细胞生物学
生物化学
作者
Yu Wang,Qianqian Zhou,Chao Liu,Ruizhe Zhang,Baocai Xing,Jie Du,Dan Lin,Jia Wei Zheng,Zhiqiang Chen,Mengyu Sun,Xiaofeng Yao,Yu Ren,Xuan Zhou
标识
DOI:10.1016/j.canlet.2024.216612
摘要
Head and neck squamous cell carcinoma (HNSCC) is featured by notorious EGFR tyrosine kinase inhibitor (TKI) resistance attributable to activation of parallel pathways. The numerous phase I/II trials have rarely shown encouraging clinical outcomes of EGFR-TKIs during treatment in HNSCC patients with advanced tumors. A unique IL-6/STAT3 signaling axis is reported to regulate multiple cancer-related pathways, but whether this signaling is correlated with reduced EGFR-TKI responsiveness is unclear. Here, we found that STAT3 signaling is compensatorily upregulated after EGFR-TKI exposure and confers anti-EGFR therapy resistance during HNSCC therapy. Targeting STAT3 using small molecule inhibitors promotes complete recovery or sustained elimination of HNSCC tumors through combination with EGFR-TKIs both in vitro and in diverse animal models. Mechanistically, phosphorylated STAT3 was proven to enhance oncogenic autophagic flux, protecting cancer cells and preventing EGFR-TKI-induced tumor apoptosis. Thus, blockade of STAT3 signaling simultaneously disrupts several key interactions during tumor progression and remodels the autophagic degradation system, thereby rendering advanced HNSCC eradicable through combination with EGFR-TKI therapy. These findings provide a clinically actionable strategy and suggest STAT3 as a predictive biomarker with therapeutic potential for EGFR-TKI resistant HNSCC patients.
科研通智能强力驱动
Strongly Powered by AbleSci AI