title: Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma.
abstract: BACKGROUND
  MAPK7/ERK5 (extracellular-signal-regulated kinase 5) functions within a canonical three-tiered MAPK (mitogen activated protein kinase) signaling cascade comprising MEK (MAPK/ERK kinase) 5, MEKK(MEK kinase) 2/3 and ERK5 itself. Despite being the least well studied of the MAPK-modules, evidence supports a role for MAPK7-signaling in the pathology of several cancer types.
  
  
  RESULTS
  Fluorescence in situ hybridization (FISH) analysis identified MAPK7 gene amplification in 4% (3/74) of non-small cell lung cancers (NSCLC) (enriched to 6% (3/49) in squamous cell carcinoma) and 2% (2/95) of squamous esophageal cancers (sqEC). Immunohistochemical (IHC) analysis revealed a good correlation between MAPK7 gene amplification and protein expression. MAPK7 was validated as a proliferative oncogenic driver by performing in vitro siRNA knockdown of MAPK7 in tumor cell lines. Finally, a novel MEK5/MAPK7 co-transfected HEK293 cell line was developed and used for routine cell-based pharmacodynamic screening. Phosphorylation antibody microarray analysis also identified novel downstream pharmacodynamic (PD) biomarkers of MAPK7 kinase inhibition in tumor cells (pMEF2A and pMEF2D).
  
  
  CONCLUSIONS
  Together, these data highlight a broader role for dysregulated MAPK7 in driving tumorigenesis within niche populations of highly prevalent tumor types, and describe current efforts in establishing a robust drug discovery screening cascade.
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Paul.gavine@astrazeneca.com.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gavine
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Mei.wang@astrazeneca.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. yudehua@yahoo.com.
authors.forename: Dehua
authors.initials: D
authors.lastname: Yu
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. eva.hu@astrazeneca.com.
authors.forename: Eva
authors.initials: E
authors.lastname: Hu
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. chunlei.huang@astrazeneca.com.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Huang
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. jenny.xia@astrazeneca.com.
authors.forename: Jenny
authors.initials: J
authors.lastname: Xia
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Xinying.su@astrazeneca.com.
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. joan.fan@astrazeneca.com.
authors.forename: Joan
authors.initials: J
authors.lastname: Fan
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Tianwei.zhang@astrazeneca.com.
authors.forename: Tianwei
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. yeqingqing616@163.com.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Li.zheng@astrazeneca.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Guanshan_zhu@hotmail.com.
authors.forename: Guanshan
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. zl_qian@aliyun.com.
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Shanghai Chest Hospital, Shanghai, People's Republic of China. luoqingquan@hotmail.com.
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Shanghai Zhongshan Hospital, Shanghai, People's Republic of China. houyingyong@medmail.com.cn.
authors.forename: Ying Yong
authors.initials: YY
authors.lastname: Hou
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Qunsheng.ji@astrazeneca.com.
authors.forename: Qunsheng
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mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004938:Esophageal Neoplasms / Q000737:chemistry / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000235:genetics*; D064326:MEF2 Transcription Factors / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C578043:MEF2D protein, human; D047428:Protein Kinase Inhibitors; D048054:Mitogen-Activated Protein Kinase 7