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Mechanisms of treatment induced cell plasticity in prostate cancer

University of British Columbia

While effective, resistance to 1st generation and 2nd generation androgen receptor (AR) pathway inhibitors is inevitable, creating a need to study the mechanisms by which prostate cancer (PCa) cells become resistant to these treatments. At its core, resistance can be categorized into AR driven and non-AR driven. The research presented in this thesis explores the hypothesis that non-AR driven resistance mechanisms exploit cellular plasticity to gain a survival advantage. Previous research has demonstrated that in response to 1st generation anti-androgens, epithelial PCa cells can undergo an epithelial-mesenchymal transition (EMT); a process implicated in metastatic dissemination of cancer cells throughout the body. Augmenting prior research demonstrating LYN tyrosine kinase’s role in resistance to 1st generation anti-androgens, our research demonstrates LYN promoting both EMT and metastasis. Specifically, we discovered that signaling cascade downstream of LYN alters the sub-cellular localization and therefore stability of key EMT promoting transcription factors Slug and Snail. While LYN does contribute to both treatment resistance and metastasis in PCa, its role in EMT was a pan-cancer mechanism observed in both breast and bladder cancer. Our research also explored the increased incidence of neuroendocrine PCa (NEPC) as a resistance mechanism to more potent 2nd generation anti-androgens (enzalutamide and abiraterone). Interrogating a model of in vivo derived enzalutamide resistance, our research uncovered the crucial role of neuronal transcription factor brain derived 2 (BRN2) in the transformation of epithelial prostate cells to neuroendocrine (NE) phenotype. Importantly, we discovered that AR inhibition relives its’ suppression of BRN2; thereby increasing BRN2 expression and initiating NE differentiation of epithelial PCa cells. Moreover, targeting BRN2 not only reduced the enzalutamide-induced NE differentiation but also reduced proliferation of enzalutamide resistant PCa cells and terminal NEPC cells. Building on this data, our research outlines the discovery of small molecule BRN2 inhibitors (BRN2i) that recapitulate the functional results demonstrated by conventional knockdown techniques. These BRN2i display specificity to BRN2 and selectivity in compromising growth of NEPC cells. Altogether, this thesis demonstrates two possible mechanisms how PCa cells alter their identity as epithelial cells to more mesenchymal (LYN) and/or neuroendocrine (BRN2) and gain resistance to AR pathway inhibitors.

Text

2019-08-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/66992

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/