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

UM-164, a Dual Inhibitor of c-Src and p38 MAPK, Suppresses Proliferation of Glioma by Reducing YAP Activity

“…In addition, YAP contains an SH3-binding domain that can directly bind to the non-receptor tyrosine kinase Src [ 52 ]. Studies also showed that Src activation mediates YAP dysregulation, invasiveness and drug resistance in tumors [ 53 , 54 ]. UM-164 was discovered as a potent Src inhibitor.…”

SDCBP promotes pancreatic cancer progression by preventing YAP1 from β-TrCP-mediated proteasomal degradation

“…Yes-associated protein 1 (YAP1) is a transcriptional coactivator downstream of the Hippo signalling pathway, which is essential for PDAC formation and development 19. YAP1 not only cooperates with KRAS in PDAC initiation but can also substitute KRAS for survival of the most aggressive subtype of advanced PDAC 20–23.…”

“…YAP1 not only cooperates with KRAS in PDAC initiation but can also substitute KRAS for survival of the most aggressive subtype of advanced PDAC 20–23. While the Hippo network is a major mechanism that controls YAP activity, recent studies have identified Hippo pathway-independent mechanisms that regulate YAP localisation and activity 19 24. The occurrence and precise significance of other modifications of YAP1 in PDAC remain largely unknown, thus, requiring further experimental work.…”

Propofol enhances stem-like properties of glioma via GABAAR‐dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism

“…Src has been reported to be an important downstream regulator of GABAergic signal transduction [ 17 , 18 ]. Src is commonly expressed in human cancers, including colon, lung, breast, and endometrial tumors [ 19 , 20 ]. Notably, Src is a major component of the processes and pathways that regulate glioblastoma (GBM) tumorigenesis, such as proliferation, invasion, migration, and the epidermal growth factor receptor, Ras/Raf/MEK, and PI3K/AKT pathways [ 2 , 21 ].…”