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Open Access Publications from the University of California

Non-genetic factors influencing drug persistence and survival in cancer cells

  • Author(s): Morinishi, Leanna
  • Advisor(s): Wu, Lani F
  • Altschuler, Steven J
  • et al.

Despite the development of new, promising therapies for treating cancer, the emergence of cancer cells that do not respond to treatment remains a major barrier to cure. These emerging populations of cancer cells can result from secondary mutations that give rise to inherited drug tolerance or resistance, but in many cases there is no clear genetic basis for improved drug survival. In fact, prior work has shown that non-genetic mechanisms (e.g. chromatin remodeling) can enable longer-term persistence of cells in drug (Sharma et al., 2010, Hinohara et al., 2018), and we and others have demonstrated that these “persister” cells are an important reservoir for the emergence of drug-resistant mutants (Ramirez et al., 2016, Hata et al., 2016). Here through a combination of data analysis, mathematical modeling, and borrowed insight from microbiology, we further our understanding of non-genetic factors that alter cancer cell response to drug treatment.

In the first chapter, I summarize literature describing the persister state in both antibiotic-treated bacteria and drug-treated cancer cells, and I highlight shared features of these persisters (such as slow growth and distinct metabolic activity). Of particular relevance to this dissertation, I discuss epigenetic and metabolic changes that influence cancer progression and drug survival. In the second chapter, I pair a close study of cancer cells differing only by expression of the epigenetic modifier TET2 with mathematical modeling to demonstrate how TET2 loss can confer a fitness advantage in drug by altering the dynamics of cell-state switching. Finally, in the third chapter, I present unpublished work focused on metabolic changes and vulnerabilities associated with TET2 loss. Through these studies, I describe several non-genetic mechanisms that affect persistence and tolerance of cancer cells in drug and highlight the challenges in pharmacologically targeting these complex and ill-defined modes of drug survival.

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