Chemical and genetic perturbations reveal wiring of the protein homeostasis network in prostate cancer
The protein homeostasis (proteostasis) network is composed of multiple components and pathways that work together to govern protein production, folding, stability and degradation. Cancer cells are especially dependent on the proteostasis network, due to their high protein load, genomic instability, and oncogenic signaling pathways. For this reason, inhibitors of the proteostasis network have been developed as anti-cancer therapies, with varying success. In this dissertation, I will discuss two adjacent strategies we employed to better understand wiring of the proteostasis network in cancer cells. In this first approach, we used existing chemical inhibitors of various proteostasis targets, such as molecular chaperones and the proteasome, and tested them in combination to reveal patterns of synergy and antagonism. In the second approach, we used a functional genomics shRNA screening approach to probe at genetic vulnerabilities in the proteostasis network and identify new targets. In both these studies, we focused our work on prostate cancer, due to it’s established dependence on molecular chaperones. Through these approaches we were able to identify both synergistic drug combinations and new proteostasis targets that can be further explored as anti-cancer therapeutic strategies. Furthermore, we gained a better understanding of proteostasis network wiring in prostate cancer cells, which provides broader insights into how to can be therapeutically targeted in cancer.