Understanding Cancer Persister Cell Vulnerabilities and Mutagenesis
- Author(s): Stuhlfire, Anna Elizabeth
- Advisor(s): Hangauer, Matthew J
- et al.
The landscape of cancer treatment options has grown to include more precise and less invasive strategies. However, acquired drug resistance often results in transient responses. Cancer persister cells are a heterogeneous subpopulation of tumor cells which survive lethal doses of anti-cancer therapy and seed tumor recurrence. Persister cells survive treatment by non-genetic mechanisms that are not well understood. Additionally, persister cells undergo stress induced mutagenesis and rapid genetic adaptation resulting in the emergence of genetically drug resistant cells. Therapeutically targeting persister cells is therefore a promising approach to prevent acquired resistance. In this thesis, we describe our investigations into persister cell vulnerabilities and mutagenesis. First, we discovered that HDAC inhibitors sensitize various types of persister cells to ferroptosis, an oxidative cell death process. Second, we describe our efforts to elucidate the mechanism by which the clinically utilized anti-alcoholism drug, Disulfiram kills persister cells. Lastly, we explore the mechanism by which persister cells undergo mutagenesis that allows for acquired genetic resistance to cancer drugs.