Abstract A20: ARHGEF2 inhibition impairs cell growth and viability in KRAS-dependent cancer cells

Sporadic tumours carrying activating mutations of the RAS family of GTPases are characterized by a progressive and multiple step tumorigenesis. Among the three isoforms, K-RAS is the most commonly mutated (Prior et al., 2012). ARHGEF2 is a microtubule-associated guanine nucleotide exchange factor (GEF) for the Rho family of small GTPases whose expression is up-regulated (more than 30 times) upon Ras neoplastic transformation in Rat fibroblasts (Zuber et al., 2000). A truncated version of the protein can transform NIH 3T3 cells (Whitehead et al., 1995) and induce tumour formation in nude mice (Brecht et al., 2005). We recently identified ARHGEF2 as a transcriptional target of the RAS/MAPK pathway and its expression contributes to cell survival and growth in RAS-transformed cells (Cullis et al., in revision). We aimed to determine if ARHGEF2 is required for tumour cell viability in different KRAS mutant cancer cell lines. We used an RNAi approach using two different ARHGEF2 and KRAS shRNAs to monitor cell growth and viability in six different cancer cell lines harbouring a KRAS mutation: four pancreatic adenocarcinomas (PL45, Panc 02.03, Panc 04.03 and KP4), one endometrial adenocarcinoma (HEC-1-A) and one colorectal adenocarcinoma (LS 174T). We found that ARHGEF2 is required for cell growth and survival in half of the cell lines analyzed. We established an ARHGEF2 and KRAS dependency index for those cell lines and further analysis allowed us to determine a positive correlation (correlation coefficient of 0.64, p value References: Prior, IA et al. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012. Zuber, J. et al. A genome-wide survey of RAS transformation targets. Nat Gen. 2000. Whitehead, I et al. Expression cloning of lfc, a novel oncogene with structural similarities to guanine nucleotide exchange factors and to the regulatory region of protein kinase C. J Biol Chem. 1995. Brecht, M. et al. Activation of gef-h1, a guanine nucleotide exchange factor for RhoA, by DNA transfection. Int J Cancer. 2005. Cullis, J. et al. The Rho GEF-H1 is required for RAS oncogene-diven pancreatic cancer. In revision. Citation Format: Maria Jose Sandi Vargas, Oliver A. Kent, Josee Normand, Robert Rottapel. ARHGEF2 inhibition impairs cell growth and viability in KRAS-dependent cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A20. doi: 10.1158/1557-3125.RASONC14-A20