埃罗替尼
奥西默替尼
变构调节
癌症研究
盐酸厄洛替尼
自分泌信号
腺癌
表皮生长因子受体
车站3
医学
药理学
信号转导
化学
内科学
生物
受体
细胞生物学
癌症
作者
Qian Liang,Miaomiao Gong,Jing-Hua Zou,Mingyu Luo,Lulu Jiang,Cheng Wang,Ning-xiang Shen,Mo-cong Zhang,Lu Xu,Hui-Min Lei,Keren Zhang,Rui Zhang,Guanglei Zhuang,Liang Zhu,Hongzhuan Chen,Lü Zhou,Ying Shen
标识
DOI:10.1016/j.drup.2023.100957
摘要
Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.
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