UBC Theses and Dissertations
Role of receptor tyrosine kinase like orphan receptor 2 in treatment-resistant prostate cancer Ahn, Chihwan (Paul)
Potent androgen receptor pathway inhibitors such as Enzalutamide (ENZ) and Abiraterone (Abi) have become the gold standard for patients with castration resistant prostate cancer (CRPC). However, treatment resistance is inevitable and all patients eventually become insensitive to these treatments. To investigate the molecular mechanism of treatment resistance in prostate cancer, our laboratory has engineered ENZ-resistant (ENZR) CRPC cell lines, which mirror clinical observations, through serial passaging of LNCaP xenografts under ENZ. Using our RNA sequencing data, we found Receptor tyrosine kinase like orphan receptor 2 (ROR2) as one of the most upregulated receptor tyrosine kinases (RTKs) in both our in vitro cell lines and patients. The oncogenic roles of ROR2 have been elucidated in various cancers, including prostate cancer. However, the role of ROR2 in context of treatment resistance in prostate cancer is still unknown. For the first time, we generated a novel ROR2 gene signature to provide insights on its role in treatment-resistant prostate cancer using RNA sequencing data of in vitro models and patients. We successfully validated the legitimacy of ROR2 gene signature in various models. Correlation studies revealed that ROR2 activity may be ligand-independent. Further examination of ROR2 gene signature revealed that ROR2 upregulates CD274 (known as programmed death-ligand 1; PD-L1) in treatment-resistant setting. Various computational studies and in vitro experiments supported and validated the novel ROR2-CD274 axis. Together, our data reveal a novel discovery of ROR2-CD274 axis in treatment-resistant prostate cancer.
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