Nahi, Narmin (2021) Biological significance and targeting HER family members and cyclin-dependent kinases in gastric cancer. (MSc(R) thesis), Kingston University, .
Abstract
Introduction: In 2018, gastric cancer was the 5th most commonly diagnosed cancer and the 3rd leading cause of cancer deaths globally, highlighting the urgent need for the development of more effective and less toxic therapeutic agents for patients with this disease. In the past three decades, increased expression and activation of the human epidermal growth factor receptor family members have been reported in a wide range of human cancers, and in some studies have also been associated with a poorer prognosis. In other studies, the expression of HER family members, other heterologous growth factor receptors (e.g., IGF-IR) and tumour heterogeneity have been associated with the poorer response to therapy with the HER inhibitors.. Therefore, the major aim of this project was to investigate the effect of various targeted agents on proliferation and migration of tumour cells, the two hallmarks of human cancer, and whether there were any associations between the expression levels of various biomarkers and the response to the treatment. Methods: The effects of 18 agents targeting different members of the HER family, cyclin dependent kinases (CDKs), other growth factor receptors or cell signalling molecules on growth and migration of a panel of human gastric cancer cell lines (GCCLs) were determined by sulforhodamine B colourimetric assay and scratch wound healing assay respectively. The relative expression of all four members of the HER family members and three other heterologous growth factor receptors (i.e., IGF-IR, C-MET and ALK7) in human GCCLs were determined using flow cytometry. Linear regression analysis was employed to determine whether there was an association between the expression level of the growth factor receptors and response to these agents. Results: Of all growth factor receptors studied, EGFR had the highest level of expression in all five human GCCLs with the mean fluorescence intensity (MFI) ranging from 469 (AGS) to 32 (HGC27), respectively. All GCCLs were also HER2 positive with the MFI value ranging from 66 (AGS) to 18 (MKN-1), respectively. With the exceptions of the cytotoxic drugs paclitaxel and docetaxel, the CDK 1/2/5/9 inhibitor dinaciclib was found to be the most effective agent and inhibited the growth of all GCCLs with an IC50 value ranging from 4nM (HGC27) to 7.6nM (MKN1). Of various types of the HER inhibitors examined, all human GCCLs were most sensitive to treatment with the irreversible pan-HER TKIs (e.g. afatinib) than to treatment with other types of HER inhibitors such as the reversible EGFR specific TKI erlotinib or the irreversible HER2 specific TKI TAK165. A significant association was only found between the IGF-IR expression and the response to treatment with the NVP-AEW742 (IGF-IR inhibitor), the IGF-IR expression and response to paclitaxel and docetaxel, and between the EGFR expression and response to treatment with the PDGFRα/β TKI crenolanib. Scratch wound healing assay demonstrated different significant results with each of the five tested agents on different cell lines and demonstrated significantly higher efficacy with afatinib and the CDK inhibitors Dinaciclib and AT7519. Conclusion: The results support the need for further studies of the relative expression, predictive value and prognostic significance of such antigens in patients with stomach cancer as well as the therapeutic potential of these agents in such patients.
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