Speaker: Stuart Schreiber, PhD
Broad Institute and Harvard University
The ability of cancer cells to resist apoptotic death induced by radiation, chemotherapy, targeted therapies and immunotherapy has been a primary impediment to achieving long-lasting clinical responses. Cancer resistance is often studied through the lens of genetics, and thus on a drug-by-drug basis. I will discuss an alternative approach -- studying resistance through the lens of cellular plasticity. Our findings are suggesting that a similar form of plasticity appears recurrently in multiple cancer contexts, thus opening the possibility of a pan-cancer explanation of resistance, wherein cell plasticity provides access to an apoptosis-deficient state and thus resistance, and then subsequent cancer mutations, rather than being the basis of resistance, are needed to optimize the fitness of the resistant state for growth. We found that this myofibroblastic-like cell state has profound changes in lipid biology that result in a novel vulnerability to ferroptotic cell death and a dependency on the activity of a druggable lipid hydroperoxidase.