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Introduction
Pancreatic cancer is one of the most common types of cancer worldwide and the fourth leading cause of cancer-associated mortality in developed countries (1,2). Pancreatic cancer is a malignant disease with a median survival time of 3–6 months and a 5-year survival rate of less than 5% (3,4). Chemotherapy is the primary adjuvant therapy for pancreatic cancer (5). Dasatinib is an oral inhibitor of dual Bcr/Abl and Src family kinases (6) commonly used in hematopoietic tumors (7). Src kinase was one of the earliest discovered proto-oncoproteins in humans, which exhibits high activity in a number of human tumors and is involved in the process of malignant transformation of cells (8). The Src-mediated tumor cell signal transduction network serves a crucial role in tumorigenic processes, such as cell growth (9). Activated Src kinase promotes cell proliferation through the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway (10). Dasatinib is also an Src inhibitor approved by the Food and Drug Administration (FDA) for the treatment of pancreatic cancer (11). A previous study reported that Dasatinib could treat epithelial neoplasms, including pancreatic cancer (12). In addition, dasatinib can slow down cancer metastasis and the progression of human pancreatic ductal adenocarcinoma (PDAC) in orthotopic mouse models, and may be able to stimulate PDAC cell apoptosis in humans and mice (13–15). Bartscht et al (16) reported that dasatinib inhibits the function of Src kinases and transforming growth factor β 1 (TGF-β1) in clinical and experimental therapeutics to prevent the metastatic spread of late-stage PDAC. Dasatinib is a highly promising treatment of pancreatic cancer; however, most patients who have a good response to inhibitors typically experience disease recurrence due to drug-resistance development, which becomes a severe clinical problem (11).
The mechanism of acquired dasatinib resistance is unclear. Previous studies reported that SRC/TGF-β alteration and multiple signals, such as the MAPK signaling pathways, may be associated with the progression of drug resistance (17,18). Beauchamp et al (19) revealed that acquired dasatinib resistance may be related to a discoidin domain receptor tyrosine kinase 2 gatekeeper mutation and the loss of neurofibromatosis type 1. These studies demonstrated that multiple genes participate in the development of dasatinib-resistance, and that alterations in multiple genes are often associated with cells resistance to dasatinib. Therefore, it is not advisable...