Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the most lethal diseases. Current evidence, discussed in this article, implicates an interplay between the oncogene KRAS, the transcriptional co-activator YES1-Associated Protein (YAP) and the proto-oncogenes of the Src family kinases (SFK) in the pathogenesis of PDAC and consequently, they represent potential targets for therapeutic intervention. Here, we focus on recent mechanistic and translational studies that identify a complex crosstalk between KRAS, YAP and SFK in PDAC initiation and maintenance. Additionally, we discuss strategies for targeting these crucial signaling nodes and the feedback loops emanating from them, with especial consideration to preventing the development of drug resistance. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a devastating disease. The purpose of this review is to highlight recent literature on mechanistic and translational developments that advance our understanding of a complex crosstalk between KRAS, YAP and Src tyrosine kinase family (SFK) in PDAC development and maintenance. We discuss recent studies indicating the importance of RAS dimerization in signal transduction and new findings showing that the potent pro-oncogenic members of the SFK phosphorylate and inhibit RAS function. These surprising findings imply that RAS may not play a crucial role in maintaining certain subtypes of PDAC. In support of this interpretation, current evidence indicates that the survival of the basal-like subtype of PDAC is less dependent on RAS but relies, at least in part, on the activity of YAP/TAZ. Based on current evidence, we propose that SFK propels PDAC cells to a state of high metastasis, epithelial-mesenchymal transition (EMT) and reduced dependence on KRAS signaling, salient features of the aggressive basal-like/squamous subtype of PDAC. Strategies for PDAC treatment should consider the opposite effects of tyrosine phosphorylation on KRAS and SFK/YAP in the design of drug combinations that target these novel crosstalk mechanisms and overcome drug resistance.