Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma

BMC Cancer

Research Article

Qingqing Ye¹  Mei Wang¹  Chunlei Huang¹  Paul R. Gavine¹  Li Zheng¹  Jenny Xia¹  Tianwei Zhang¹  Dehua Yu¹  Xinying Su¹  Guanshan Zhu¹  Joan Fan¹  Eva Hu¹  Qunsheng Ji¹  Ziliang Qian¹  Qingquan Luo²  Ying Yong Hou³ 

[1] Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, 201203, Shanghai, People’s Republic of China;Shanghai Chest Hospital, Shanghai, People’s Republic of China;Shanghai Zhongshan Hospital, Shanghai, People’s Republic of China;

关键词: MAPK7;    ERK5;    Oncogene;    Kinase;    Inhibitor;   

DOI  :  10.1186/s12885-015-1455-y

 received in 2014-11-05, accepted in 2015-05-20,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundMAPK7/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 resultsFluorescence 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).ConclusionsTogether, 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.

【 授权许可】

CC BY   
© Gavine et al.; licensee BioMed Central. 2015