Copper Conducted Kinase Signaling in Cancer
Donita Brady, Ph.D.
Harrison McCrea Dickson, M.D., and Clifford C. Baker, M.D., Presidential Professor, Department of Cancer Biology
Assistant Dean for Inclusion, Diversity, and Equity in Research Training
Associate Investigator, Abramson Family Cancer Research Institute
Perelman School of Medicine, University of Pennsylvania
Pioneers in Biomedical Research Seminar: Copper Conducted Kinase Signaling in Cancer
Date: Nov. 18, 2022
Time: 11 a.m. - 12 p.m.
About this Seminar
Kinases respond to and, in some cases, sense inputs such as growth factors, nutrients, and metabolites, in order to relay information that drives complex cellular processes. Aberrant kinase activation disrupts the balance between cell growth and cell death and, consequently, can drive cancer initiation and progression. While kinase inhibitors have dramatically changed the landscape of cancer treatment, the near-universal emergence of resistance limits their clinical durability. Dr. Brady’s research program is founded in a new paradigm in nutrient sensing and protein regulation, termed metalloallostery, whereby redox-active metals control kinase activity. The laboratory’s focus lies at the intersection of kinase signaling and copper (Cu) homeostasis with the goal of defining the mechanisms regulating Cu-dependent kinases in order to target them in cancer through drug development or repurposing. Previously Dr. Brady’s team discovered that the transition metal Cu, which is acquired as a dietary nutrient and is essential for life, activates the canonical MAPK signaling pathway at the level of the MEK1/2 kinases established an evolutionarily conserved, critical mechanistic function for Cu as an intracellular mediator of signaling. The direct interaction between Cu and MEK1/2 is the first example of Cu enhancing the activity of a mammalian kinase and revealed a novel vulnerability that can be exploited therapeutically in cancers with aberrant MAPK signaling. Beyond the Cu-MEK1/2 interaction, Brady’s lab discovered that Cu binds to, and is required for, ULK1/2 activity, thereby serving as a critical input for ULK1/2-dependent autophagy. Dual targeting of MAPK signaling and ULK1/2-driven autophagy by limiting Cu availability and, therefore, kinase Cu binding, decreased oncogenic KRAS-driven tumor growth and survival. These findings chart new ground in nutrient signaling, cellular energy homeostasis, and metabolic vulnerabilities in cancer, further establish Cu as a signaling molecule, define the molecular basis for a new Cu-dependent cellular process, and exploit Cu-dependent kinases to target oncogene-driven dependencies. The emergence of this new and clinically relevant signaling paradigm has highlighted the need to understand how redox-active metals interact with signaling pathways and underscores the promise of discovering new modes of kinase regulation as orthogonal therapeutic vulnerabilities.
Additional Details
This is a free event hosted by the Fralin Biomedical Research Institute and co-sponsored by the institute's Cancer Research Group. The Pioneers in Biomedical Research Seminar Series, which runs annually from September to May, has featured leading biomedical researchers from throughout the country since the program began in 2012. The lectures are also open to all members of the Virginia Tech community including graduate students, undergraduates, faculty, and staff, as well as the public.
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