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Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is intractable to currently available treatment modalities (Vincent et al. 2011). Failure of standard chemo-, radioand neoadjuvant single pathway targeted therapies indicate that before newer treatment regimens are designed, one has to re-visit the basic understanding of the origins and complexity of PDAC. As such, PDAC is now appreciated to have not only a highly heterogeneous pathology but is also a disease characterized by dysregulation of multiple pathways governing fundamental cell processes (Kim and Simeone 2011). Such complexity has been suggested to be governed by molecular networks that execute metabolic or cytoskeletal processes, or their regulation by complex signal transduction originating from diverse genetic mutations (Figure 1). A major challenge, therefore, is to understand how to develop actionable modulation of this multivariate dysregulation, with respect to both how it arises from diverse genetic mutations and to how it may be ameliorated by prospective treatments in PDAC. Lack of understanding in both these areas is certainly a major underlying reason for failure of most of the available and clinically used drugs (Stathis and Moore 2010). The pharmaceutical industry handpicked drugs have been generally based on their specificity towards a particular protein and the subsequent targeted pathway (K-Ras, PI3K, MEK, EGFR, p53 etc) without considering the effect of modulating secondary and interacting pathways (Almhanna and Philip 2011; Philip 2011). However, as results from integrated network modeling and systems biology studies indicate, targeting one protein is not straightforward as each protein in a cellular system works in a complex interacting network comprised of a myriad interconnected pathways (Wist et al. 2009a). Silencing one protein/pathway can have multiple effects on different secondary pathways leading to secondary effects. For example, activation of salvage pathways (commonly observed in PDAC) can result in diminished drug response or in some cases acquired resistance. Therefore, in order to decode this complexity and to understand both the PDAC disease and identify drug targets, it requires a departure from a protein-centric to a more advanced network-centric view. This chapter deals with recent advancements on deciphering PDAC disease networks and drug response networks based on integrated systems and network biology-driven science. It is believed that such integrated and holistic approach will help in not only delineating the mechanism of resistance of this complex disease, it will also aid in the future design of targeted drug combinations that will improve the dismal cure rate.

Systems and Network-Centric Understanding of Pancreatic Ductal Adenocarcinoma Signalling