Abstract
The proto-oncogene nonreceptor tyrosine-protein kinase SRC is a member of the SRC family of tyrosine kinases (SFKs), and its activation and overexpression have been shown to play a protumorigenic role in multiple solid cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is currently the seventh-leading cause of cancer-related death worldwide, and, by 2030, it is predicted to become the second-leading cause of cancer-related death in the United States. PDAC is characterized by its high lethality (5-year survival of rate of <10%), invasiveness, and chemoresistance, all of which have been shown to be due to the presence of pancreatic cancer stem cells (PaCSCs) within the tumor. Due to the demonstrated overexpression of SRC in PDAC, we set out to determine if SRC kinases are important for PaCSC biology using pharmacological inhibitors of SRC kinases (dasatinib or PP2). Treatment of primary PDAC cultures established from patient-derived xenografts with dasatinib or PP2 reduced the clonogenic, self-renewal, and tumor-initiating capacity of PaCSCs, which we attribute to the downregulation of key signaling factors such as p-FAK, p-ERK1-2, and p-AKT. Therefore, this study not only validates that SRC kinases are relevant and biologically important for PaCSCs but also suggests that inhibitors of SRC kinases may represent a possible future treatment option for PDAC patients, although further studies are still needed.
Highlights
It is generally accepted that the majority of solid tumors contain a small subpopulation of highly plastic, tumorigenic, and chemoresistant cells, known as cancer stem cells (CSCs), that are the drivers of tumor evolution, metastasis, and disease relapse [1,2,3]
We verified these findings in publicly available transcriptome pancreatic ductal adenocarcinoma (PDAC) datasets that have become available over the past 10 years (META dataset [51], Jandaghi et al [52], The Cancer Genome Atlas (TCGA; http://xena.ucsc.edu), and Janky et al [53])
In the study by Janky et al, samples were classified as normal pancreas, early or advanced PDAC, and lymph node metastasis (LNM)
Summary
It is generally accepted that the majority of solid tumors contain a small subpopulation of highly plastic, tumorigenic, and chemoresistant cells, known as cancer stem cells (CSCs), that are the drivers of tumor evolution, metastasis, and disease relapse [1,2,3]. PDAC represents the seventh leading cause of cancer-related death worldwide; it is predicted to soon become the third leading cause of cancer death in the European Union [14] and the second in the United States [15] While these alarming statistics can be attributed to the fact that PDAC is typically diagnosed at advanced stages, due to a lack of both symptoms and sensitive/specific markers for early detection [16], the existence of pancreatic CSCs (PaCSCs) [17,18] likely plays an important role in the poor prognosis of this disease and contributes to the inherent aggressiveness as well as the chemotherapy- and radiotherapy-resistant nature of this tumor. Inhibitors of SRC kinases can certainly affect PaCSCs and the data presented support the continued evaluation of these inhibitors as possible treatment options, likely in combination with standard of care, for PDAC
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