Exploiting quiescent state vulnerability to deplete cytostatic cancer cells
2019-12
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Exploiting quiescent state vulnerability to deplete cytostatic cancer cells
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2019-12
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Abstract
Controlling cancers as chronic conditions, by arresting and sustaining tumor cells at a quiescent or non-proliferating cytostatic state, is emerging as a standard treatment approach with the increasing use of targeted therapies for cancers. While effective, persisting cytostatic tumor cells pose fundamental challenges to achieving prolonged effects as they require continual maintenance and are prone to develop resistance and recurrence. Depleting these tumor populations could improve treatment outcome, but no rational approach exists, besides monitoring, because no targeting strategy is designed for non-proliferating cells. Here, we exploited vulnerabilities evoked by oncogenic signals at quiescent states to devise targeting strategies for cytostatic tumor populations harboring AKT hyperactivation, an oncogenic change associated with treatment-tolerance and relapse. Using an organotypic model of normal quiescent mammary cells, we found that AKT hyperactivation dysregulates redox and protein homeostasis and sensitizes the quiescent cells to apoptosis upon proteasome inhibition in a p70S6K- and redox-dependent manner. Intriguingly, therapeutic exploitation of this AKT-driven quiescent-state proteasome-vulnerability showed efficacies on cytostatic cancer cells with aberrant PI3K/AKT signaling activation across different breast cancer subtypes, epithelial tissue origins, and arresting mechanisms. Moreover, transient proteasome-inhibitor treatment in spheroid and mouse xenograft models of cytostatic tumors significantly reduced recurrent growth after treatment-cessation. Our work highlights the effects of oncogenic mutations on altering homeostasis at non-proliferating states that could form the basis for devising targeted approaches for depleting genetically-predisposed cytostatic tumor subpopulations.
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University of Minnesota Ph.D. dissertation. 2019. Major: Pharmacology. Advisor: Cheuk Leung. 1 computer file (PDF); 118 pages + 2 supplementary files.
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Kim, Lisa. (2019). Exploiting quiescent state vulnerability to deplete cytostatic cancer cells. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/219309.
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