Abstract 2157: Targeting the Maternal Embryonic Leucin zipper Kinase (MELK) in gastric cancers.
Authors: Julie G. Izzo, Kevin N. Dalby, Han Liang, Hui Yao, Brian P. James, Saira Ahmed, Xiuping Liu, Chang-Gong Liu, Yon Hui Kim, Garth Powis
Journal: Cancer Research (2013)

Abstract Gastric cancer (GC) is the fourth most common cancer, and the second leading cause of cancer-related death in the world. The high mortality rate of gastric cancer is due to late-stage diagnosis and unpredictable outcome with empiric treatments. There are no tools to stratify therapies for ERBB2-negative GC (90% of patients). Even in ERBB2-positive patients, much better therapies are desirable. To identify novel GC drivers and therapeutic targets, we conducted a whole-transcriptome RNA-seq analysis in Caucasian cancers and paired normal gastric tissues. We identified 879 differentially expressed genes with FDR&amp;lt;0.01 &amp; fold change (FC) &amp;gt;2. We next compared our results with those of Cui J. et al. (Nucl. Acids Res. 2011) which identified differential expressions in 80 tumor-normal pairs of Asian GC. With an FDR &amp;lt;0.01 &amp; FC&amp;gt;2, we found 308 genes overlapping, including 30 kinases. Among the kinases, we found consistent high expression of the Maternal Embryonic Leucine zipper Kinase (MELK), the only member of the member of the Snf1/AMPK serine/threonine kinase family not regulated by LKB1 kinase, but rather through autophosphorylation. MELK is putatively involved in mitotic progression, inhibition of mRNA splicing, cytokinesis, and apoptosis. MELK overexpression has been found in other cancers, including human glioblastoma and breast cancers where it promotes tumorigenesis and portends to worse outcome. The precise in vivo regulation, function and crystal/NMR structures of MELK are still unknown; however the evidence that three MELK substrates are critical regulators of the mitotic entry, underscores the hypothesis that MELK inhibition may offer important novel therapeutic strategy. We investigated MELK protein expression in a panel of 30 gastric cell lines, and found high levels of MELK protein in 14/30. Similar results were observed in a panel of 22 colon carcinoma lines. MELK blockade using siRNA affected cytokinesis with the formation of polynucleated cells and aberrant mitotic spindle. Ongoing in vitro and in vivo investigations include cells with MELK knockdown by shRNA as well as MELK -/-, MELK +/+ cells, and MELK point mutation cells generated by Zinc Finger Nuclease Technology, and cells carrying MELK kinase dead; and identification of novel small compounds inhibiting MELK activity. Because of the increased expression in a broad spectrum of cancer sites, and the putative role in orchestrating mitotic entry, we believe that MELK offers important targeted therapeutic windows: 1) it will enhance the efficacy of antineoplastic drugs targeting mitosis; 2) by hindering the ability of tumor initiating cells to proliferate, it will impact the repopulation phase following chemo-radiation therapy, and therefore could be incorporated into molecular targeted strategies circumventing resistance to conventional therapy in MELK positive cancers. Citation Format: Julie G. Izzo, Kevin N. Dalby, Han Liang, Hui Yao, Brian P. James, Saira Ahmed, Xiuping Liu, Chang-Gong Liu, Yon Hui Kim, Garth Powis. Targeting the Maternal Embryonic Leucin zipper Kinase (MELK) in gastric cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2157. doi:10.1158/1538-7445.AM2013-2157 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.