首页|Tet methylcytosine dioxygenase 2(TET2)deficiency elicits EGFR-TKI(tyrosine kinase inhibitors)resistance in non-small cell lung cancer
Tet methylcytosine dioxygenase 2(TET2)deficiency elicits EGFR-TKI(tyrosine kinase inhibitors)resistance in non-small cell lung cancer
扫码查看
点击上方二维码区域，可以放大扫码查看
原文链接
NETL
NSTL
万方数据
Despite epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKI)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 CUL7FBXW11 and degraded in EGFR-TKI resistant NSCLC cells.Genetic perturbation of 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 CUL7FBXW11.Loss of TET2 resulted in the upregulation of TNF/NF-κB signaling that confers the EGFR-TKI resistance.Genetic or pharmacological inhibition of NF-κB 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.
Department of Thoracic Surgery and Institute of Thoracic Oncology,West China Hospital of Sichuan University,Chengdu 610097,China
Western China Collaborative Innovation Center for Early Diagnosis and Multidisciplinary Therapy of Lung Cancer,Sichuan University,Chengdu 610097,China
Biobank of West China Hospital,Sichuan University,Chengdu 610041,China
国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金1.3.5 Project for Disciplines of Excellence1.3.5 Project for Disciplines of Excellence1.3.5 Project for Disciplines of Excellence1.3.5 Project for Disciplines of Excellence中国博士后科学基金中国博士后科学基金四川省自然科学基金
NETL
NSTL
万方数据
