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.
Highlights
One of the deadliest types of cancer has been and still is pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer (~90%)
Our own work with human Pancreatic ductal adenocarcinoma (PDAC) cells that correspond to the basal-like/squamous subtype [154] demonstrated that crosstalk between insulin/IGF-1 receptor and G protein-coupled receptors (GPCRs) signaling systems [155,156] induces robust nuclear Yes-Associated Protein (YAP) localization, decreases phosphorylation at sites targeted by LATS1/2 and stimulates transcriptional co-activator activity through phosphatidylinositol 3-kinase (PI3K)
We recently found that stimulation of human pancreatic cancer cells with a combination of the GPCR agonist neurotensin and insulin induces a marked increase in YAP phosphorylation at Tyr357, which was prevented by exposure to Src family of tyrosine kinases (SFKs) inhibitors
Summary
One of the deadliest types of cancer has been and still is pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer (~90%). A recent report of the American Cancer Society estimates 60,430 new cases (28,480 females and 31,950 males) of pancreatic cancer in the year 2021. 25,270 male patients) will succumb to this disease, putting pancreatic cancer as the third leading cause of cancer mortality in the USA [1]. The 5-year survival rate in PDAC has stayed at around 9%. These sobering statistics provide strong impetus to search for novel strategies for early diagnosis and for identifying new targets, agents and combinatorial approaches for prevention and therapeutic intervention. The elucidation of the molecular mechanisms driving PDAC growth and dissemination will be of crucial significance to guide the discovery of novel biomarkers, targets and agents for therapeutic intervention. Multiple other therapies for the treatment of PDAC are under development [5], including targeting epigenetic control [6], the extracellular matrix and the immune system [7] but their discussion is beyond the scope of this article
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