title: TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.
abstract: 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.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Applied Physics, School of Science, Xi'an Jiaotong University, Xi'an, China.|Engineering Research Center of Forest Bio-preparation, Ministry of Education, Northeast Forestry University, Harbin, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.|Department of Pulmonary Medicine, Xi'an Ninth Hospital, Xi'an, China.
authors.forename: Shudi
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Niu
authors.affiliation: Department of Applied Physics, School of Science, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Shengli
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Lintao
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Shengqing
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D064593:Heterografts; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D011897:Random Allocation; D014162:Transfection
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase; D000077156:Gefitinib
keywords: AP-1; EGFR-TKI resistance; TOPK; c-Jun; lung cancer