Abstract 1765: Ras and EF-hand domain containing as a novel tissue biomarker and a therapeutic target for lung cancer

Abstract

Abstract Lung cancer is the most common cause of cancer-related death in the world and its incidence has been increasing. The number of patients responding well to current standard therapies is still small, therefore further development of new agents targeting cancer-specific molecules with no or minimum risk of adverse effect is urgently awaited. To screen molecules, particularly oncoantigens which could be useful for the development of diagnostic biomarkers and new drugs, we have established an effective screening strategy as follows; i) To identify up-regulated genes in 120 lung cancers by genome-wide screening using the cDNA microarray representing 27,648 genes and pure populations of tumor cells taken from cancer tissues by laser microdissection, ii) To verify the candidate genes for their very low or absent expression in normal tissues by northern-blot analyses, iii) To validate the clinicopathological significance of their expression with tissue microarray containing hundreds of archived lung cancers, iv) To verify whether the target genes are essential for the growth or survival of cancer cells by RNAi and cell growth assays. As a result of this process, we identified 40 druggable oncoproteins. We further identified the Ras and EF-hand domain containing (RASEF), which contains a Rab GTPase domain and is considered as a member of Rab GTPase protein family. Immunohistochemical staining using tumor tissue microarrays consisting of 341 archived non-small cell lung cancers revealed the association of strong RASEF positivity with poor prognosis (P = 0.0034 by multivariate analysis). Reduction in RASEF expression by siRNA suppressed lung cancer cell proliferation, while induction of RASEF conferred growth-promoting activity of mammalian cells. RASEF could bind to extracellular signal-regulated kinase (ERK) 1/2 and appeared to enhance the ERK1/2 signaling. In addition, inhibition of interaction between RASEF and ERK1/2 using cell-permeable peptide that corresponded to the ERK1/2-interacting site of RASEF protein, suppressed growth of lung cancer cells. RASEF may play important roles in lung carcinogenesis, and could be useful as a prognostic biomarker and a target for the development of new molecular therapies. Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Ras and EF-hand domain containing as a novel tissue biomarker and a therapeutic target for lung cancer. [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 1765. doi:10.1158/1538-7445.AM2014-1765