Genetic Dissection of Cancer Drug Resistance and Toxicity Using Haploid Human Cells
Toxicity and resistance to chemotherapy drugs remain major hurdles in oncology. My proposal is focused on using an emerging genetic strategy called "haploid genetic screening" to discover genes that mediate resistance to topoisomerase inhibitors, chemotherapeutics which form the backbone of treatment for several cancers. An initial screen with the Topoisomerase II inhibitor doxorubicin has revealed previously unknown mechanisms that mediate resistance, including a potential role for chromatin-regulatory complexes as well as a novel mechanism of transcriptional regulation of a gene encoding a drug efflux pump.
I propose to perform a comprehensive set of haploid screens using both Topoisomerase I and II inhibitors to uncover genes that mediate responses to these agents. In-depth analysis will be used to understand the mechanism by which hits from my doxorubicin screen and the additional proposed screens influence sensitivity to these agents. These studies have the potential to reveal the mechanisms by which topoisomerases function in the physiological chromatin context in intact cells and to uncover new strategies to mitigate toxicities and ameliorate resistance for patients receiving these agents.