2. Academic Validation
  3. 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

  • Signal Transduct Target Ther. 2024 Mar 9;9(1):65. doi: 10.1038/s41392-024-01778-4.
Jian Zhang # 1 2,  Kejia Zhao # 1 2,  Wenjing Zhou 1 2,  Ran Kang 1 2,  Shiyou Wei 1 2,  Yueli Shu 1 2,  Cheng Yu 1 2,  Yin Ku 1 2,  Yonghong Mao 1 2,  Hao Luo 1 2,  Juqin Yang 3,  Jiandong Mei 1,  Qiang Pu 1,  Senyi Deng 1 2,  Zhengyu Zha 1 2,  Gang Yuan 1 2,  Shensi Shen 1 2,  Yaohui Chen 4 5,  Lunxu Liu 6 7
Affiliations

Affiliations

  • 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.
  • 4 Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital of Sichuan University, Chengdu, 610097, China. yhchen@scu.edu.cn.
  • 5 Western China Collaborative Innovation Center for Early Diagnosis and Multidisciplinary Therapy of Lung Cancer, Sichuan University, Chengdu, 610097, China. yhchen@scu.edu.cn.
  • 6 Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital of Sichuan University, Chengdu, 610097, China. lunxu_liu@aliyun.com.
  • 7 Western China Collaborative Innovation Center for Early Diagnosis and Multidisciplinary Therapy of Lung Cancer, Sichuan University, Chengdu, 610097, China. lunxu_liu@aliyun.com.
  • # Contributed equally.
PMID: 38461173 DOI: 10.1038/s41392-024-01778-4
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z