Research Papers:

TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun

Ying Li, Zhiwei Yang, Weijie Li, Shudi Xu, Tao Wang, Ting Wang, Mengjie Niu, Shengli Zhang, Lintao Jia and Shengqing Li _

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Oncotarget. 2016; 7:6748-6764. https://doi.org/10.18632/oncotarget.6826

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Ying Li1,*, Zhiwei Yang2,5,*, Weijie Li1,*, Shudi Xu1,6,*, Tao Wang4, Ting Wang3, Mengjie Niu1, Shengli Zhang2, Lintao Jia3 and Shengqing Li1

1 Department of Pulmonary and Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, China

2 Department of Applied Physics, School of Science, Xi’an Jiaotong University, Xi’an, China

3 State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi‘an, China

4 Department of Neurology, Shaanxi Provincial People’s Hospital, Xi’an, China

5 Engineering Research Center of Forest Bio-preparation, Ministry of Education, Northeast Forestry University, Harbin, China

6 Department of Pulmonary Medicine, Xi’an Ninth Hospital, Xi’an, China

* These authors have contributed equally to this work

Correspondence to:

Shengqing Li, email:

Lintao Jia, email:

Keywords: TOPK, lung cancer, EGFR-TKI resistance, c-Jun, AP-1

Received: June 21, 2015 Accepted: December 31, 2015 Published: January 06, 2016


Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have shown promising clinical efficacy in non-squamous non-small cell lung cancer (NSCLC); however, resistance is frequently observed in malignant cells, operating through a mechanism that remains largely unknown. The present study shows that T-lymphokine-activated killer cell-originated protein kinase (TOPK) is upregulated in NSCLC and excessively activated in TKI-refractory cells. TOPK dictates the responsiveness of lung cancers to the EGFR-targeted TKI gefitinib through the transcription factor AP-1 component c-Jun. TOPK binds directly to and phosphorylates c-Jun, which consequently activates the transcription of AP-1 target genes, including CCND1 and CDC2. TOPK silencing sensitizes EGFR-TKI-resistant lung cancer cells to gefitinib and increases gefitinib efficacy in preclinical lung adenocarcinoma xenograft models. These findings represent a novel mechanism of lung cancer resistance to TKIs and suggest that TOPK may have value both as a predictive biomarker and as a therapeutic target: TOPK-targeted therapy may synergize with EGFR-targeted therapy in lung cancers.

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