PMID- 26040563 OWN - NLM STAT- MEDLINE DCOM- 20160301 LR - 20181113 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 15 DP - 2015 Jun 4 TI - Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma. PG - 454 LID - 10.1186/s12885-015-1455-y [doi] LID - 454 AB - 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. METHODS AND 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. FAU - Gavine, Paul R AU - Gavine PR AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Paul.gavine@astrazeneca.com. FAU - Wang, Mei AU - Wang M AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Mei.wang@astrazeneca.com. FAU - Yu, Dehua AU - Yu D AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. yudehua@yahoo.com. FAU - Hu, Eva AU - Hu E AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. eva.hu@astrazeneca.com. FAU - Huang, Chunlei AU - Huang C AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. chunlei.huang@astrazeneca.com. FAU - Xia, Jenny AU - Xia J AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. jenny.xia@astrazeneca.com. FAU - Su, Xinying AU - Su X AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Xinying.su@astrazeneca.com. FAU - Fan, Joan AU - Fan J AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. joan.fan@astrazeneca.com. FAU - Zhang, Tianwei AU - Zhang T AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Tianwei.zhang@astrazeneca.com. FAU - Ye, Qingqing AU - Ye Q AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. yeqingqing616@163.com. FAU - Zheng, Li AU - Zheng L AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Li.zheng@astrazeneca.com. FAU - Zhu, Guanshan AU - Zhu G AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Guanshan_zhu@hotmail.com. FAU - Qian, Ziliang AU - Qian Z AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. zl_qian@aliyun.com. FAU - Luo, Qingquan AU - Luo Q AD - Shanghai Chest Hospital, Shanghai, People's Republic of China. luoqingquan@hotmail.com. FAU - Hou, Ying Yong AU - Hou YY AD - Shanghai Zhongshan Hospital, Shanghai, People's Republic of China. houyingyong@medmail.com.cn. FAU - Ji, Qunsheng AU - Ji Q AD - Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. Qunsheng.ji@astrazeneca.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150604 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Biomarkers, Tumor) RN - 0 (MEF2 Transcription Factors) RN - 0 (MEF2A protein, human) RN - 0 (MEF2D protein, human) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 7) SB - IM MH - Biomarkers, Tumor/metabolism MH - Carcinoma, Squamous Cell/chemistry/*genetics MH - Cell Proliferation/genetics MH - *Drug Screening Assays, Antitumor MH - Esophageal Neoplasms/chemistry/*genetics MH - Gene Expression Regulation, Neoplastic MH - Gene Knockdown Techniques MH - HEK293 Cells MH - Humans MH - Lung Neoplasms/chemistry/*genetics MH - MEF2 Transcription Factors/metabolism MH - Mitogen-Activated Protein Kinase 7/analysis/antagonists & inhibitors/*genetics MH - Phosphorylation MH - Protein Kinase Inhibitors/*pharmacology MH - Signal Transduction PMC - PMC4453990 EDAT- 2015/06/05 06:00 MHDA- 2016/03/02 06:00 PMCR- 2015/06/04 CRDT- 2015/06/05 06:00 PHST- 2014/11/05 00:00 [received] PHST- 2015/05/20 00:00 [accepted] PHST- 2015/06/05 06:00 [entrez] PHST- 2015/06/05 06:00 [pubmed] PHST- 2016/03/02 06:00 [medline] PHST- 2015/06/04 00:00 [pmc-release] AID - 10.1186/s12885-015-1455-y [pii] AID - 1455 [pii] AID - 10.1186/s12885-015-1455-y [doi] PST - epublish SO - BMC Cancer. 2015 Jun 4;15:454. doi: 10.1186/s12885-015-1455-y.