My laboratory uses tools from pharmacology, genomics, and cell signaling to study two key aspects of cancer biology. First, we seek to understand how oncogenic signals, altered metabolic states, and drug therapies impact cell death regulation in cancer, with a particular focus on the mitochondrial cell death pathway (for example, Science Translational Medicine 2016, 8, ra175; Nature Communications 2018, 9, 1677; Nature Communications 2018, 9, 3513; Cell Metabolism 2019, 29, 1217; Science Translational Medicine 2022, 14, eabc7480). Second, we seek to understand the mechanisms that shape tumor evolution under the selective pressure of drug treatments, with the long-term goal of creating therapies that select against resistance (for example, Cell Reports 2017, 21, 2796; Cancer Discovery 2020, 10, 1894; Nature Genetics 2020, 52, 408; Nature Cancer 2022, 3, 837). A common theme in nearly all of our studies is the coupling of large-scale, unbiased genomic and pharmacological approaches with mechanistic studies using the classic tools of biochemistry and molecular and cellular biology. Collectively, our studies have led to new, fundamental mechanistic insights into the core survival circuitry operating in defined human tumor subsets as well as novel translational therapeutics. In this talk, I will highlight ways we have used functional genomics, and in particular CRISPR/Cas9-based loss-of-function screens, to define mechanistic determinants of apoptotic commitment and vulnerabilities associated with acquired drug resistance.

Learning objectives:
1. Discuss ways that CRISPR screens can reveal mechanistic determinants of cell fate
2. Relate ways in which drug modifier CRISPR screens can reveal drug mechanisms of action and resistance
3. Highlight translational applications of discoveries made using cancer-focused functional genomics