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作 者:Jian Zhang Kejia Zhao Wenjing Zhou Ran Kang Shiyou Wei Yueli Shu Cheng Yu Yin Ku Yonghong Mao Hao Luo Juqin Yang Jiandong Mei Qiang Pu Senyi Deng Zhengyu Zha Gang Yuan Shensi Shen Yaohui Chen Lunxu Liu
机构地区:[1]Department of Thoracic Surgery and Institute of Thoracic Oncology,West China Hospital of Sichuan University,Chengdu 610097,China [2]Western China Collaborative Innovation Center for Early Diagnosis and Multidisciplinary Therapy of Lung Cancer,Sichuan University,Chengdu 610097,China [3]Biobank of West China Hospital,Sichuan University,Chengdu 610041,China
出 处:《Signal Transduction and Targeted Therapy》2024年第4期1706-1720,共15页信号转导与靶向治疗(英文)
基 金:supported by the National Natural Science Foundation of China (Grants 31771549 to Y.C.,82103251 to J.Z.,82203153 to K.Z.,and 82203574 to S.W.);the 1.3.5 Project for Disciplines of Excellence (Grants ZYGD18021,ZYJC18009,ZYJC21002,and ZYJC21015);the China Postdoctoral Science Foundation (Grants 2020TQ0210 and 2021M692268 to J.Z.);Natural Science Foundation of Sichuan Province (Grant 2022NSFSC1438 to J.Z.).
摘 要:Despite epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKl)have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer(NSCLC),acquired resistance inevitably develops,limiting clinical efficacy.We found that TET2 was poly-ubiquitinated by E3 ligase CUL7^(FBXW11) and degraded in EGFR-TKI resistant NSCLC ells.Genetic perturbationof TET2 rendered parental cells more tolerant to TKI treatment.TET2 was stabilized by MEK1 phosphorylation at Ser 1107,while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7^(FBXW11),Loss of TET2 resulted in the upregulation of TNF/NF-kB signaling that confers the EGFR-TKI resistance.Genetic or pharmacological inhibition of NF-kB attenuate the TKI resistance both in vitro and in vivo.Our findings exemplified how a cell growth controlling kinase MEK1 leveraged the epigenetic homeostasis by regulating TET2,and demonstrated an alternative path of non-mutational acquired EGFR-TKI resistance modulated by TET2 deficiency.Therefore,combined strategy exploiting EGFR-TKI and inhibitors of TET2/NF-κB axis holds therapeutic potential for treating NSCLC patients who suffered from this resistance.
关 键 词:TET2 TKI RESISTANCE
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