Abstract 2923: Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma
Authors: Paul R. Gavine, Mei Wang, Dehua Yu, Eva Hu, Chunlei Huang, Jenny Xia, Xinying Su, Joan Fan, Tianwei Zhang, Qingqing Ye, Li Zheng, Liang Xie, Luna Han, Guanshan Zhu, Ziliang Qian, Qingquan Luo, Yingyong Hou, Qunsheng Ji
Journal: Cancer Research (2014)

Abstract MAPK7/ERK5 (extracellular-signal-regulated kinase 5) is the effector kinase of a canonical three-tiered MAPK (mitogen activated protein kinase) signalling cascade comprising MEK (MAPK/ERK kinase) 5, MEKK(MEK kinase) 2/3 and ERK5 itself(1). Under normal physiological conditions, MEK5 and ERK5 are ubiquitously expressed and are activated by growth factors and cellular stresses to perform roles in blood vessel, cardiac and muscle development(2). Although the MAPK7-axis is the least well studied of the MAPK-signaling pathways, evidence suggests that it plays a role in the pathology of cancer, in particular; breast cancer progression, prostate cancer bone metastases and hepatocellular carcinoma(3-5). Array-based comparative genomic hybridisation profiling (aCGH) of non-small cell lung cancer (NSCLC) patient tumor samples initially identified MAPK7 gene amplification as a novel genetic event. To further explore the role of MAPK7 in human cancer, we assessed the true incidence of MAPK7 gene amplification using fluorescence in situ hybridization (FISH) analysis in a cohort of 80 NSCLC and 95 squamous esophageal cancers (sqEC). High level MAPK7 gene amplification was detected in 4% (3/80) of NSCLC (enriched to 6% (3/49) in squamous cell carcinoma) and 2% (2/95) of sqEC. Immunohistochemical (IHC) analysis of the same tissue samples revealed a good correlation of MAPK7 gene amplification and high level protein expression but importantly, also identified a high prevalence of IHC ‘3+’ MAPK7 protein expression (20% - 15/74 NSCLC) in the absence of gene amplification. To validate MAPK7 as an oncogenic driver of tumor cell proliferation, we performed in vitro siRNA knockdown of MAPK7 in amplified and non-amplified tumor cell lines. Potent anti-proliferative effects were only observed when MAPK7 protein expression was ablated in MAPK7-amplified lines (eg. KYSE30). To support drug discovery efforts, a novel MEK5/MAPK7 co-transfected HEK293 cell line was developed and used for routine cell-based pharmacodynamic screening. In parallel, reverse-phase protein arrays (RPPA) were used to identify novel candidate downstream pharmacodynamic biomarkers of MAPK7 kinase inhibition in tumor cells (pMEF2A and pMEF2C). Finally, a novel MAPK7-amplified esophageal xenograft model was established and used to demonstrate direct pharmacodynamic modulation of pMAPK7 using a commercially available tool compound (XMD8-92). Taken 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. 1. Zhou, G. (1995) J. Biol. Chem. 270, 12665-12669 2. Lochhead PA. (2012) Biochem Soc Trans. 40(1):251-6. 3. Song, H. (2004) Oncogene 23, 8301-8309 4. Mehta, P.B. (2003) Oncogene 22, 1381-1389 5. Zen, K. (2009) Genes Chromosomes Cancer 48,109-120 Citation Format: Paul R. Gavine, Mei Wang, Dehua Yu, Eva Hu, Chunlei Huang, Jenny Xia, Xinying Su, Joan Fan, Tianwei Zhang, Qingqing Ye, Li Zheng, Liang Xie, Luna Han, Guanshan Zhu, Ziliang Qian, Qingquan Luo, Yingyong Hou, Qunsheng Ji. Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2923. doi:10.1158/1538-7445.AM2014-2923