Abstract A1: SNAIL inhibitor GN-25 induces MET through Global Reprograming of EMT Network Genes: a Systems and Network Analysis

Abstract

Abstract Epithelial-to-mesenchymal transition (EMT) is a complex mechanism that arises through a cohesive and intricate biological cross-talk between numerous cancer-related networks. Among them sonic hedgehog directed snail network is one of the major components that drives EMT. This has led to strategies targeting either hedgehog signaling or snail protein using highly specific agents. However, it is needless to say that removal of individual components through single protein-targeted drug (here snail) from robust EMT networks may surprisingly have little functional consequence in cancer. We propose that, to have an impact, interventions within EMT network need to be multiple but highly selective. Further, predicting the functional outcome of interventions, such as those originating from single pathway targeted drug treatment, is not as straightforward as originally thought and computational/integrated tools are needed. The emergence of computational network biology has enhanced our knowledge of multi-pathway interactions in cancer and helped in making sense of drug response signature datasets that collectively decode the complex mechanisms of drug action. These holistic approaches have laid the foundation of the emerging concepts of “network pharmacology” that is solidifying its position in cancer medicine. Unlike earlier reductionist one-drug, one-target approaches, network pharmacology invokes the idea of drug promiscuity often engages a fortuitous combination of appropriate high-value targets in cancer cells to produce treatment success. Network pharmacology is being used in the identification of weak nodes in global cancer networks, predicting drug toxicity, drug repurposing, identifying multiscale mechanisms of drug action and in the rational design of potent anticancer drug combinations. To this end, we had earlier developed a novel snail-p53 interaction inhibitor (GN-25) that was shown to suppress snail function. However, this drug was not investigated for its effects against EMT pathways. Here using network pharmacology drug repurposing principles, we show that our novel SNAIL inhibitor (GN-25), through its promiscuous action induces mesenchymal-to-epithelial transition (MET) in well-recognized HMLE-snail cell line model developed by Dr. Weinberg. Network modeling of microarray gene expression profiling data from GN-25 treated cells showed an orchestrated global reorganization of EMT network genes. Most importantly, the expression signatures were validated both at the mRNA and protein expression levels, and mechanistically studied by RNA interference which provided unequivocal evidence on the role of GN-25 targeting EMT specific genes. This proof-of-concept investigation shows that computational biology and network pharmacology can be very powerful tools for rational design and development of agents that are typically promiscuous like the snail inhibitor as a candidate EMT-targeting drug. Citation Format: Asfar S. Azmi, Ramzi M. Mohammad, Fazlul H. Sarkar. SNAIL inhibitor GN-25 induces MET through Global Reprograming of EMT Network Genes: a Systems and Network Analysis [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A1.