Keynote Presentation: Systematic identification of therapeutic strategies that leverage tumor evolution

Our laboratory uses tools from pharmacology, genomics, and cell signaling to identify new precision anticancer therapeutic strategies. Under this broad heading, our work involves three key areas of emphasis. First, we use custom functional and structural genomic tools to define the landscape of signaling pathways capable of driving resistance to therapy (for example, Science Signaling 2012, 5, rs4; Science Signaling 2014, 7, ra121; and Cell Reports 2017, 20, 999). Second, we utilize knowledge of resistance landscapes to identify new therapeutic strategies that have the potential to circumvent resistance evolution (for example, Science Signaling 2014, 7, ra122; Nature Communications 2017, 8, 15617; Cell Reports 2017, 21, 2796; Nature Communications 2018, 9, 4274; Science Advances 2019, 5, eaaw9162; and Nature Genetics 2020, 52, 408). Finally, we use unbiased approaches to define mechanism-based, targetable vulnerabilities in human cancers for application to malignancies characterized by “undruggable” genetic drivers or immunologically “cold” microenvironments, where in many cases these vulnerabilities center on the dysregulated structure and function of tumor mitochondria (for example, Science Translational Medicine 2016, 8, ra175; Nature Communications 2018, 9, 1677; Nature Communications 2018, 9, 3513; and Cell Metabolism 2019, 29, 1217). Collectively, these studies are leading to both fundamental new insights into the core survival circuitry operating in defined human tumor subsets as well as novel translational therapeutics. In this talk, I will provide an overview of our work, with a particular focus on studies that have identified mechanisms of convergent tumor evolution and associated strategies to leverage this phenomenon to build combination therapies that select against resistance.

Learning Objectives:
1. Understand strategies for designing mechanism-based combination therapies to overcome resistance

2. Learn examples of convergent resistance evolution

3. Use functional genomics and pharmacological screening to identify therapeutic targets