The mTORC1 protein kinase is a master nutrient sensor and metabolic regulator. In response to the combined action of nutrient, growth factor and energy inputs, mTORC1 triggers biosynthetic processes and suppresses catabolism, leading to cell growth and proliferation. Aberrant mTORC1 activity is increasingly recognized as a driving force in human diseases ranging from cancer to type-2 diabetes to neurodegeneration, making mTORC1 a prime therapeutic target. However, due to its complex layout and inherent adaptability, the mTORC1 pathway has so far remained refractory to pharmacological manipulations in disease settings. Here I will present our recent work aimed at 1- reconstituting fundamental aspects of mTORC1 regulation both in vitro and cell-based systems n 2- identifying and characterizing new-generation compounds that inhibit mTORC1 both potently and selectively. I will also discuss how these studies lay the foundations for gene-editing strategies aimed at discovering new therapeutic targets in the mTORC1 pathway and anticipating mechanisms of drug resistance in cancer settings.
Dissecting and Reconstituting Lysosome-based Nutrient Sensing in Health and Disease
Assistant Professor, Department of Molecular and Cell Biology