Abstract
In the scenario of personalized medicine, targeted therapies are currently the focus of cancer drug development. These drugs can block the growth and spread of tumor cells by interfering with key molecules involved in malignancy, such as receptor tyrosine kinases (RTKs). MET and Recepteur d’Origine Nantais (RON), which are RTKs frequently overactivated in gastric cancer, are glycoprotein receptors whose activation have been shown to be modulated by the cellular glycosylation. In this work, we address the role of sialylation in gastric cancer therapy using an innovative 3D high-throughput cell culture methodology that mimics better the in vivo tumor features. We evaluate the response to targeted treatment of glycoengineered gastric cancer cell models overexpressing the sialyltransferases ST3GAL4 or ST3GAL6 by subjecting 3D spheroids to the tyrosine kinase inhibitor crizotinib. We show here that 3D spheroids of ST3GAL4 or ST3GAL6 overexpressing MKN45 gastric cancer cells are less affected by the inhibitor. In addition, we disclose a potential compensatory pathway via activation of the Insulin Receptor upon crizotinib treatment. Our results suggest that cell sialylation, in addition of being involved in tumor progression, could play a critical role in the response to tyrosine kinase inhibitors in gastric cancer.
Highlights
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer related deaths worldwide [1]
We have evaluated the role of increased α2,3-sialylation in gastric cancer therapy using an innovative 3D high-throughput cell culture methodology on a MET amplified GC cell line
Our results show that 3D spheroids of MKN45 overexpressing the sialyltransferases ST3GAL4 and ST3GAL6 are less sensitive to crizotinib treatment
Summary
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer related deaths worldwide [1]. The activation of RTKs is frequently altered in GC, and around 37% of patients may be potentially treatable with RTK/RAS-directed therapies [4,5] Among these RTKs, the hepatocyte growth factor receptor (HGFR), known as MET, has been widely studied to be involved in the oncogenesis of a large number of tumors [6]. The MET receptor signaling pathway is frequently overactivated in gastric cancer [6,8] Another relevant RTK is the Recepteur d’Origine Nantais (RON) ( known as macrophage-stimulating protein receptor (MSPR) or MST1R) which commonly shows aberrant activation in various tumors due to overexpression and generation of oncogenic variants [9,10]. Alterations in the cellular glycosylation has been shown to modulate the activation of MET and RON in GC [11,12,13]
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