In the KC model, mutated is expressed from its endogenous locus (by crossing mice with or mice, mutations have also been shown to be important for PDAC maintenance[51,52]. and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators. MUTATIONS AND PDAC Oncogenic mutations were first reported to be associated with PDAC more than 30 years ago[11,12]. Although the genetic landscape of PDAC is complex, since the initial reports extensive research in both UVO humans and mice have substantiated the critical significance of mutations in the early stages of PDAC. In fact, many studies have confirmed that over 90% of PDAC harbors mutations[13,14] and KRAS signaling is one of the core signaling pathways in human PDAC[13]. Most mutations in PDAC are found at position G12, of which the NMDA solitary amino acid substitute G12D is the most predominant[15]. Mutations at position G13 or Q61 have been recognized at lower rate of recurrence, 21% NMDA or 28%, respectively[15]. Using deep whole exome sequencing a genomic characterization of PDAC exposed several different mutations inside a subset of tumors, with some PDACs showing biallelic mutations[16]. NMDA Mechanistically, mutations at position G12 with a single amino acid substitution induce conformational changes that interfere with the intrinsic GTPase activity of KRAS and prevent the relationships between KRAS and GTPase-activating proteins (GAPs), which stimulate the conversion of KRAS-GTP (active state) to KRAS-GDP (inactive state), thereby ending KRAS activation. In this manner, the KRAS mutations lead to its long term activation and consequently to the prolonged activation of downstream signaling effectors[15,17]. It is becoming obvious that different mutations of G12 lead to different conformational claims that differ in their affinity for interacting effectors[18]. Although mutations in is an early and essential step in PDAC, it is insufficient to stimulate development of frank, invasive PDAC. Activation of additional pathways by additional mutations (or mutations[43]. This getting provided further evidence in support of the step-wise carcinogenesis model, in which mutations are envisioned as initiating events[15,44,45]. Genetically manufactured mouse models of PDAC have corroborated this paradigm[46-49]. In the KC model, mutated is definitely indicated from its endogenous locus (by crossing mice with or mice, mutations have also been shown to be important for PDAC maintenance[51,52]. Good notion that mutated is necessary but not fully sufficient for the development of invasive PDAC, only few animals (5%-10%) in the KC model (without additional genetic alterations) develop frank PDAC very late (usually after 9 mo)[46]. Cell senescence has been proposed like a barrier to the malignant progression of tumors[53]. The formation of PDAC can be greatly accelerated by the presence of another mutation (in murine models efficiently transformed only a small percentage of cells[60]. KRAS downstream signaling molecules, including the ERKs were not triggered when oncogenic was indicated from its endogenous locus[61]. Accordingly, cell culture studies have shown that incubating PDAC cells inside a serum-free medium failed to display activated ERK despite the presence of activating mutations in these cells. However, ERK activation could be induced by adding growth factors to the culture medium[62-64]. In mouse models, oncogenic in adult mice was insufficient to induce PDAC, while concomitant induction of.